Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present

ABSTRACT

The present invention relates to compounds of the formula: ##STR1## These compounds are useful in pharmaceuticals in which cannabis is known to be involved.

The present application is a continuation-in-part application of U.S. Ser. No. 08/168,237, filed Dec. 17, 1993, now abandoned, which is a continuation-in-part application of U.S. Ser. No. 08/079,870, filed Jun. 23, 1993, now abandoned.

The present invention relates to novel pyrazole derivatives, to a method of preparing them and to the pharmaceutical compositions in which they are present.

Numerous pyrazole derivatives have been described in the literature; more particularly, EP-A-268554 and DE-A-3910248 claim pyrazoles possessing herbicidal properties, EP-A-430186 and JP-A-03031840 claim compounds useful for photography, and EP-A-418845 claims pyrazoles possessing antiinflammatory, analgesic and antithrombotic activity.

It has now been found that the pyrazoles forming the subject of the invention have a good affinity for the cannabinoid receptor and are therefore particularly valuable in the therapeutic areas in which cannabis is known to be involved.

Δ⁹ -Tetrahydrocannabinol, or Δ⁹ -THC, is the main active constituent extracted from Cannabis sativa (Tuner, 1985; In Marijuana 84, Ed. Harvey, D. Y., IRL Press, Oxford).

The effects of cannabinoids are due to an interaction with specific high-affinity receptors present in the central nervous system (Devane et al., Molecular Pharmacology, 1988, 34, 605-613) and peripheral nervous system (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791; Kaminski et al., 1992, Molecular Pharmacology, 42, 736-742; Munro et al., Nature, 1993, 365, 61-65).

Characterization of this receptor has been made possible by the development of specific synthetic ligands such as the agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247, 1046-1051).

The therapeutic indications of cannabinoids pertain to a variety of areas such as the immune system, the central nervous system and the cardiovascular or endocrine system (Hollister, Pharmacological Reviews, 1986, 38, 1-20, Renv and Sinha, Progress in Drug Research, 1991, 36, 71-114, Cannabinoid receptor expression in human leucocytes, European Journal of Biochemistry, 1993, 214, 173-180.

More particularly, compounds possessing an affinity for the cannabinoid receptor are useful as lmmunomodulators and psychotropic agents, in thymic disorders, vomiting, myorelaxation, various types of neuropathy, memory disorders, dyskinesia, migraine, asthma, epilepsy and glaucoma or else in anticancer chemotherapy, in ischemia and angor, in orthostatic hypotension and in cardiac insufficiency.

Thus, according to one of its features, the present invention relates to the compounds of the formula ##STR2## in which

g₂, g₃, g₄, g₅ and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical or different and are independently hydrogen, a chlorine or bromine atom, a (C₁ -C₃)-alkyl, a (C₁ -C₃)alkoxy, a trifluoromethyi or a nitro group and g₄ is optionally a phenyl group;

R₄ is hydrogen or a (C₁ -C₃)-alkyl;

X is either a direct bond or a group --(CH₂)_(x) N(R₃)--, in which R₃ is hydrogen or a (C₁ -C₃)-alkyl and x is zero or one; and

R is

a group --NR₁ R₂ in which R₁ and R₂ are independently a (C₁ -C₆)-alkyl; an optionally-substituted non-aromatic (C₃ -C₁₅) carbocyclic radical; an amino (C₁ -C₄) alkyl group in which the amino is optionally disubstituted by a (C₁ -C₃)-alkyl; a cycloalkyl-(C₁ -C₃) alkyl in which the cycloalkyl is C₃ -C₁₂ ; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, by a (C₁ -C₅)-alkyl or by a (C₁ -C₅)-alkoxy; a phenyl (C₁ -C₃)-alkyl; a diphenyl-(C₁ -C₃)-alkyl; a naphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclic radical which is unsubstituted or substituted by a (C₁ -C₃)-alkyl, by a hydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromatic heterocycle unsubstituted or mono-or-polysubstituted by a halogen, a (C₁ -C₅)alkyl, a (C₁ -C₅)-alkoxy; a (C₁ -C₃)-alkyl substituted by an aromatic heterocycle unsubstituted or mono- or -polysubstituted by a halogen, a (C₁ -C₅) alkyl, a (C₁ -C₅)-alkoxy, or else R₁ is hydrogen and R₂ is as defined above, or else R₁ and R₂, together with the nitrogen atom to which they are bonded, form a saturated 5- to 8-membered heterocyclic radical, said heterocyclic radical being other than morpholine when w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ are all hydrogen;

a group R₂ as defined above when X is --(CH₂)_(x) N(R₃)--; or

a group R₅ when X is a direct bond, R₅ being a (C₁ -C₃)-alkyl; a (C₃ -C₁₂)-cycloalkyl which is unsubstituted or substituted by a (C₁ -C₅)-alkyl; a phenyl-(C₁ -C₃)-alkyl which is unsubstituted or substituted by a halogen or by a (C₁ -C₅)-alkyl; a cycloalkyl-(C₁ -C₃)-alkyl in which the cycloalkyl is C₃ -C₁₂ and is unsubstituted or substituted by a (C₁ -C₅)-alkyl; or a 2-norbornylmethyl; or one of their salts, where appropriate.

The non-aromatic C₃ -C₁₅ carbocyclic radicals include saturated or unsaturated, fused or bridged monocyclic or polycyclic radicals, optionally terpene radicals. These radicals are optionally mono- or polysubstituted, said substiituent(s) being different from a substituted carbonyl group. Advantageously, the monocyclic radicals are substituted by at least one group selected among the (C₁ -C₅) alkyl, (C₁ -C₅)alkoxy, halogen or hydroxy groups, it being understood that in the case of terpenes or terpene radicals, for example bornyl, menthyl or menthenyl, the alkyl groups of the terpene are not considered as substituents.

The monocyclic radicals include cycloalkyls, for example cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl, which are unsubstituted or substituted by at least one (C₁ -C₅)-alkyl, (C₁ -C₅)-alkoxy, halogen or hydroxy groups.

The fused, bridged or spiranic dicyclic or tricyclic radicals include for example norbornyl, bornyl, isobornyl, noradamantyl, adamantyl and spiro[5,5]undecanyl, said radicals being unsubstituted or substituted by a (C₁ -C₅)-alkyl.

Saturated 5- to 8-membered heterocyclic radical is understood as meaning a fused or bridged, non-aromatic monocyclic, dicyclic or tricyclic heterocyclic radical, the heteroatom being S, O or N, or a non-aromatic monocyclic heterocyclic radical containing a nitrogen atom and an oxygen or sulfur atom, said radicals being for example tetrahydrofuranyl, tetrahydrothiofuranyl, tropyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl or quinuclidinyl, the 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl radicals being advantageous.

The aromatic heterocycles can be monocyclic or dicyclic, for example pyrrolyl, pyridyl, indolyl, quinolinyl, thiazolyl or isoindazolyl, these aromatic heterocycles being unsubstituted or substituted for example by halogens, (C₁ -C₅)-alkyl or (C₁ -C₅)-alkoxy. The prefered aromatic heterocycles are pyridyl, pyrrole, indole groups, the radicals 2-indolyl or 3-indolyl are particularly prefered.

In formula (I) above, preferably at least one of the substituents w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ is other than hydrogen.

In formula (I) above, when R is a Group --NR₁ R₂, preferably:

R₁ is hydrogen or a (C₁ -C₆)-alkyl group and R₂ is as defined above for (I); or

R₁ and R₂ are each a (C₁ -C₆)-alkyl group or a (C₃ -C₆)-cycloalkyl group; or

R₁ is hydrogen or a (C₁ -C₆)-alkyl group and R₂ is a cycloalkyl-(C₁ -C₃)-alkyl group in which the cycloalkyl is C₃ -C₁₂ ; a non-aromatic (C₃ -C₁₅) carbocyclic radical which is unsubstituted or substituted as above mentioned; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, by a (C₁ -C₃)-alkyl or by a (C₁ -C₃)-alkoxy; a phenyl-(C₁ -C₃)-alkyl or a (C₁ -C₃)alkyl substituted by a 2- or 3-indolyl.

Particularly preferably, when R in formula (I) is a group --NR₁ R₂, R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a non-aromatic (C₃ -C₁₅) carbocyclic radical, a cycloalkyl-(C₁ -C₃)-alkyl in which the cycloalkyl is C₃ -C₆, or a 2- or 3-indolyl-(C₁ -C₃)-alkyl.

The preferred alkyl groups are methyl, ethyl, propyl and isopropyl.

In formula (I) above, R is advantageously a group --NR₁ R₂ preferably selected from the radicals (1) to (74) below.

When R₁ and R₂, with the nitrogen atom to which they are bonded, are a heterocyclic, radical, this is preferably a 5-, 6- or 7-membered saturated heterocycle and can contain another heteroatom, especially oxygen or sulfur, for example a pyrrolidine, a piperidine, a hexahydroazepine, a morpholine or a thiomorpholine, with the limitation specified above.

The radicals represented by R as defined for (I) are preferably radicals selected from:

(1) propylamino

(2) butylamino

(3) isopropylamino

(4) dipentylamino

(5) 2-(N,N-diethylamino)ethylamino

(6) benzylamino

(7) 2-phenylethylamino

(8) 3-phenylpropylamino

(9) 3,3-diphenylpropylamino

(10) phenylamino

(11) 3-chlorophenylamino

(12) 4-methylphenylamino

(13) cyclopropylamino

(14) cyclopentylamino

(15) cyclohexylamino

(16) cycloheptylamino

(17) cyclooctylamino

(18) cyclododecylamino

(19) 2-methylcyclohexylamino

(20) 3-methylcyclohexylamino

(21) cis-4-methylcyclohexylamino

(22) trans-4-methylcyclohexylamino

(23) cis-4-tert-butylcyclohexylamino

(24) trans-4-tert-butylcyclohexylamino

(25) 4-hydroxycyclohexylamino

(26) 2-methoxycyclohexylamino

(27) 4-ethylcyclohexylamino

(28) 2,6-dimethylcyclohexylamino

(29) N-methylcyclohexylamino

(30) N,N-dicyclohexylamino

(31) endo-2-norbornylamino (or endo-bicyclo[2.2.1]-heptan-2-amino)

(32 ) exo-2-norbornylamino (or exo-bicyclo[2.2.1]heptan-2-amino)

(33) 1-adamantylamino

(34) 2-adamantylamino

(35) 1-noradamantylamino

(36) (1R)-bornylamino

(37) (1R)-isobornylamino

(38) spiro[5.5]undecanylamino

(39) cyclohexylmethylamino

(40) 1-adamantylmethylamino

(41) (2-tetrahydrofuranyl)methylamino

(42) 2-(N-methyl-2-pyrrolyl)ethylamino

(43) 2-(2-pyridinyl)ethylamino

(44) (2-indolyl)methylamino

(45) N-methyl(2-indolyl)methylamino

(46) 2-(3-indolyl)ethylamino

(47) N-methyl-2-(3-indolyl)ethylamino

(48) 4-(N-benzylpiperidinyl)amino

(49) 3-quinuclidylamino

(50) exo-bicyclo[3.2.1]octan-2-amino

(51) bicyclo[2.2.2]octan-2-amino

(52) 3-chlorobicyclo[3.2.1]oct-3-en-2-amino

(53) bicyclo[2.2.2]oct-2-en-5-amino

(54) exo-bicyclo[3.2.1]octan-3-amino

(55) endo-bicyclo[3.2.1]octan-3-amino

(56) endo-7-oxabicyclo[2.2.1]heptan-2-amino

(57) exo-7-oxabicyclo[2.2.1]heptan-2-amino

(58) endo-tricyclo[5.2.1.0²,6 ]decan-8-amino

(59) N-ethyl-1-adamantylamino

(60) tricyclo[2.2.1.0²,6 ]heptan-3-amino

(61) bicyclo[3.3.1]nonan-9-amino

(62) endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amino (or fenchylamino)

(63) (1R, 2S-endo )-(+)-bicyclo[2.2.1]heptan-2-amino

(64) (1R,2R-exo)-(-)-bicyclo[2.2.1]heptan-2-amino

(65) (1S,2R-endo)-(-)-bicyclo[2.2.1]heptan-2-amino

(66) (1S,2S-exo)-(+)-bicyclo[2.2.1]heptan-2-amino

(67) 1-piperidinylamino

(68) 1-pyrrolidinylamino

(69) 1-hexahydroazepinylamino

(70) 4-morpholinylamino

(71) 4-thiomorpholinylamino

(72) N-methyl-exo-bicyclo[2.2.1]heptan-2-amino

(73) N-ethyl-exo-bicyclo[2.2.1]heptan-2-amino

(74) N-propyl-exo-bicyclo[2.2.1]heptan-2-amino

Of the products of formula (I) above, those of formula (Ia) below are advantageous; in particular, the compounds of formula (Ia'): ##STR3## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined above for (I), R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a non-aromatic C₃ -C₁₅ carbocyclic radical or a saturated 5- to 8-membered heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl, and their salts, are particularly advantageous.

Of the products of formula (I), those of formulae (Ia), (Ib), (Ic), (Id), (Ie) and (If) below, in which at least one of the substituents w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ is other than hydrogen, R₁ is hydrogen or a (C₁ -C₆)-alkyl, R₂ is as defined above, R₃ is hydrogen or a (C₁ -C₃)-alkyl group, R₄ is hydrogen or methyl and R₅ is a cycloalkyl-(C₁ -C₃)-alkyl, the cycloalkyl being C₃ -C₆, or a phenyl-(C₁ -C₃)-alkyl which is unsubstituted or substituted on the aromatic ring by a methyl group or a fluorine or chlorine atom, and their salts, where appropriate, are particularly advantageous.

In these latter particularly advantageous products,

when R₁ is a (C₁ -C₆)-alkyl, the methyl, ethyl, propyl and isopropyl groups are preferred;

when R₃ is a (C₁ -C₃)-alkyl, the methyl group is preferred;

the preferred groups R₂ are non-aromatic C₃ -C₁₅ carbocyclic radicals which are unsubstituted or substituted by a (C₁ -C₄)-alkyl, especially methyl, ethyl, propyl, isopropyl or t-butyl, or by two or three methyl groups, for example a methyl-, ethyl- or t-butyl-cyclohexyl radical or a dimethyl- or trimethylcyclohexyl radical, cycloalkyl-(C₁ -C₃)- alkyl radicals in which the cycloalkyl is C₃ -C₆ ; (C₁ -C₃)-alkyl radicals substituted by a 2- or 3-indolyl group; 2- and 3-indolyl radicals; and 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl radicals; and

the preferred groups R₅ are cyclohexylmethyl, cyclohexylethyl, benzyl, 4-methylbenzyl and phenethyl radicals.

Of the products of formula (I) above, those of formula (i): ##STR4## in which R₄, X and R are as defined-above for (I), and their salts, are very advantageous, especially when R₄ is hydrogen or a methyl group or when R₄ is hydrogen or methyl and X is a direct bond.

The compounds of formula (i) in which R₄ is hydrogen or methyl, X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen or a methyl group and R₂ is a non-aromatic C₃ -C₁₅ carbocyclic radical or a saturated 5- to 8-membered heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl, and their salts, are particularly preferred.

Especially preferred is the compound of formula (i) in which R₄ is methyl, X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen and R₂ is 1-piperidinyl, as well as its pharmaceutically acceptable salts and their solvates.

Other particularly preferred compounds of formula (i) are those in which R₄ is hydrogen or methyl, X is --(CH₂)_(x) N(R₃)-- and R is --NR₁ R₂, x being zero or one, R₁ being hydrogen, R₃ being hydrogen or a methyl group and R₂ being a phenyl which is unsubstituted or substituted by one or two halogen atoms, a (C₁ -C₅)-alkyl group or a (C₁ -C₅)-alkoxy group, or a non-aromatic C₃ -C₁₅ carbocyclic radical, and their salts.

Of the compounds of formula (I), those of formula (ii): ##STR5## in which X and R are as defined above for (I) and w₄ is a methyl or methoxy group, especially those of formula (ii) in which w₄ is a methyl or methoxy group, X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen or a methyl group and R₂ is a non-aromatic C₃ -C₁₅ carbocyclic radical, and their salts, are also advantageous.

An advantageous subclass comprises the compounds of formula (ii) in which w₄ is a methyl or methoxy group, X is a group --(CH₂)_(x) N(R₃)-- in which x is zero or one and R₃ is hydrogen or a methyl group, and R is a group --NR₁ R₂ in which R₁ is hydrogen and R₂ is a phenyl which is unsubstituted or substituted by one or two halogen atoms, a (C₁ -C₅)-alkyl group or a (C₁ -C₅)-alkoxy group, or a non-aromatic C₃ -C₁₅ carbocyclic radical, or their salts.

Other valuable compounds according to the present invention are those of formula (I) in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ and X are as defined above for (I) and R is a group --NR₁ R₂ in which R₁ is hydrogen or a (C₁ -C₆)-alkyl group and R₂ is a 2- or 3-indolyl-(C₁ -C₃)-alkyl group or a 2- or 3-indolyl group, and their salts.

Of the latter, the products of formula (iii): ##STR6## in which X is as defined above for (I), R is a group --NR₁ R₂ in which R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a 2- or 3-indolyl-(C₁ -C₃)-alkyl group or a 2- or 3-indolyl group, and either w₂ is hydrogen and w₄ is a methyl or methcxy group or w₂ and w₄ are a chlorine atom, and their salts, are particularly valuable.

Of the products included in formula (I) above, those of formula (iv): ##STR7## in which X and R are as defined above for (I) and g₄ is a bromine atom or a methyl or trifluoromethyl, and their salts, are also valuable.

In preferred products of formula (iv), the two chlorine atoms are in the 2,3-, 2,4-, 2,5- or 3,4-positions, and in these preferred products of formula (iv), those in which X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a non-aromatic carbocyclic radical containing from 3 to 15 carlDon atoms are particularly preferred.

The salts, where appropriate, of the compounds according to the present invention, especially of those of formulae (I), (Ia'), (i), (ii) and (iii) above and (Ia), (Ib), (Ic), (Id), (Ie) and (If) below, include both those with mineral or organic acids which permit a suitable separation or crystallization of the products, such as picric acid or oxalic acid, and those with acids which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, oxalate, maleate, fumarate, naphthalene-2-sulfonate, glyconate, gluconate, citrate, isethionate and paratoluenesulfonate.

According to another of its features, the present invention relates to a method of preparing the compounds (I), which comprises treating a pyrazole-3-carboxylic acid derivative of the formula ##STR8## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined for (I), or one of its activated forms, namely one of its esters or acid chlorides, * either with an amine of the formula HNR₁ R₂, in which R₁ and R₂ are as defined for (I), to give the amides of the formula ##STR9## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄, R₁ and R₂ are as defined for (I), * or optionally with a primary amine R₃ NH₂, in which R₃ is as defined for (I), to give the intermediate amides (V) of the formula ##STR10## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ and R₃ are as defined for (I), to give, by reduction with a metal hydride, the intermediate amines of the formula ##STR11## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ and R₃ are as defined for (I), which are converted to the amide or urea of the formula ##STR12## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₂, R₃ and R₄ are as defined for (I), by reaction with an acid chloride of the formula R₂ COCl or, respectively, an isocyanate of the formula R₂ --N═C═O, in which R₂ is as defined for (I), * or with a diphenylphosphoryl azide derivative in a basic medium, followed by an acid treatment, to give the intermediate amine of the formula ##STR13## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined for (I), which is reacted with an acid chloride R₂ COCl or an isocyanate R₂ --N═C═O to give respectively the amides and ureas of the formulae ##STR14## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined for (I) and R₃ is hydrogen, the same compounds in which R₃ is other than hydrogen being prepared from the above primary amine (VII) converted to a secondary amine of the formula ##STR15## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined for (I) and R'₃ is (C₁ -C₂)-alkyl, which are then reacted with an acid chloride R₂ COCl or an isocyanate R₂ --N═C═O to give the amides and ureas of formulae (Id) and (Ie) as defined above in which R₃ is other than hydrogen, * or with an organomanganous reagent R₅ MnX₁, in which R₅ is as defined for (I) and X₁ is a halogen, to give the ketone derivatives of the formula ##STR16## the resulting compounds then being converted to one of their salts, where appropriate.

In a preferential procedure, the pyrazoles of formula (I) can be synthesized from the corresponding esters by conversion of the ester group to an amide, urea or ketone via the acid and the acid chloride.

Said esters are synthesized by applying the method described in Berichte, 1887, 20, 2185.

The reaction scheme for the preparation of the compounds (I) via their methyl or ethyl esters (Alk═CH₃ or C₂ H₅) is represented by SCHEME 1 below: ##STR17##

The first step a) consists in preparing an alkali metal salt of an acetophenone derivative of formula (IV), in which R₄ and g₂, g₃, g₄, g₅ and g₆ are as defined above for (I), to which an equimolar amount of diethyl oxalate is then added (step b) to give the ketoester of formula (III).

In the case where R₄ ═H, the alkali metal will preferably be sodium and the salt of the ketoester (III) (Alk═CH₃) will be obtained according to Bull. Soc. Chim. Fr., 1947, 14, 1098, using sodium methylate in methanol to perform step a).

In the case where R₄ ═CH₃, the alkali metal will preferably be lithium and the salt of the ketoester (III) (Alk═C₂ H₅) will be obtained according to J. Heterocyclic Chem. 1989, 26, 1389, using the lithium salt of hexamethyldisilazane in ethyl ether to perform step a).

The alkali metal salts (III) prepared in this way are then refluxed in acetic acid with an excess of a hydrazine derivative (step c). Precipitation in iced water gives the 3-pyrazole esters (IIa).

These esters (IIa) are then converted to their acids (IIb) by reaction with an alkaline agent, for example potassium hydroxide, followed by acidification (step d).

In SCHEME 1 above, the esters of formula (IIa) in which w₂ and w₄ are a chlorine atom, w₃, w₅ and w₆ are hydrogen, g₄ is a chlorine atom, g₂, g₃, g₅ and g₆ are hydrogen and Alk is a (C₁ -C₅)-alkyl, and the corresponding acids (IIb), are novel key intermediates for the preparation of the particularly advantageous compounds (i) and therefore represent a further feature of the invention; these compounds have formula (II'a) or (II'b): ##STR18##

When X is a direct bond, the amides according the invention of formula (Ia): ##STR19## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₁, R₂ and R₄ are as defined for (I), are prepared from a functional derivative of the acids (IIb), preferably a chloride, by the usual methods so that said acids (IIb) can be substituted by an amine of the formula HNR₁ R₂, prepared by the usual methods, to give the compounds (Ia) according to the invention.

For example, when it is desired to prepare a compound of formula (Ia) in which g₂, g₃, g₅, g₆, w₃, w₅ and w₆ are hydrogen, g₄, w₂ and w₄ are a chlorine atom, R₄ is methyl, R₁ is hydrogen and R₂ is 1-piperidinyl (namely N-piperidino-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), a functional derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid (a compound of formula (II'b) in which R₄ is methyl) is reacted with 1-aminopiperidine in an organic solvent in the presence of a base. The acid chloride, the anhydride, the mixed anhydride, a straight or branched C₁ -C₄ alkyl ester, an activated ester such as p-nitrophenyl ester, or the free acid appropriately activated, for example by N,N-dicyclohexylcarbodiimide or benzotriazol-N-oxotris(dimethylamino)phosphonium hexafluorophosphate (BOP) can be used as the functional derivative of the acid.

Thus, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxylic acid chloride, obtained by reaction of thionyle chloride with 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid, can be reacted with 1-aminopiperidine in a solvent such as dichloromethane in an inert atmosphere, at a temperature between 0° C. and room temperature, in the presence of a base such as triethylamine.

Alternately, the mixed anhydride of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid can be prepared by reaction of ethylchloroformate with the said acid in the presence of a base such as triethylamine, and then reacted with 1-aminopiperidine in a solvent such as dichloromethane in an inert atmosphere, at a temperature between 0° C. and room temperature, in the presence of a base such as triethylamine.

When X is a group --(CH₂)_(x) N(R₃)--, in which x and R₃ are as defined for (I), the amides and the ureas according to the invention of formulae (Ib) and (Ic): ##STR20## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₂, R₃ and R₄ are as defined for (I), are prepared from the above-described ester (IIa) according to SCHEME 2 below: ##STR21##

The conversion of the ester (IIa) to the intermediate amide (V) can be effected for example via the corresponding acid chloride, the latter being reacted with an amine R₃ NH₂ in an alkanol such as ethanol.

The reduction of the amide (V) to the amine (VI) is then effected by means of a metal hydride such as lithium aluminum hydride or, preferably, by means of the complex BH₃ -THF in solution in THF under reflux. The amine (VI) is then converted to the amide (Ib) or the urea (Ic) according to the invention by the conventional methods, for example by reaction with an acid chloride R₂ COCl or an isocyanate R₂ --N═C═O, respectively.

The amides and the ureas according to the invention of formulae (Id) and (Ie): ##STR22## in which g₂, g₃, g₄, g₅ and g₆, w₂, w₃, w₄, w₅ and w₆ and R₂, R₃ and R₄ are as defined for (I), are prepared from the previously obtained pyrazole-3-carboxylic acids according to SCHEME 3 below: ##STR23##

The acids (IIb) are converted to the corresponding amines (VII) by means of a Curtius reaction, for example using diphenylphosphoryl azide in a basic medium, followed by a treatment with a strong acid such as hydrochloric acid or trifluoroacetic acid, as described in Synthesis, 1990, 295. The amines (VII) are then converted to the amides (Id) or ureas (Ie) according to the invention by the usual methods, for example by reaction with an acid chloride R₂ COCl in the case of (Id) where R₃ ═H, or with an isocyanate R₂ --N═C═O in the case of (Ie) where R₃ ═H.

Alternatively, the ureas (Ie) where R₃ ═H can be prepared by the reverse reaction: the acids (IIb) are converted to corresponding isocyanates (VIIc) as described in J. Org. Chem. 1961, 26, 3511, according to SCHEME 4 below.

Reaction of the isocyanates (VIIc) with an amine R₂ NH₂ then gives the ureas (Ie) directly. ##STR24##

To prepare the compounds (Id) and (Ie) in which R₃ is other than hydrogen, the primary amines (VII) are first converted to secondary amines (VIIb) by a reaction sequence such as reaction with an acid chloride R'₃ COCl (where R'₃ ═(C₁ -C₂) alkyl), followed by reduction of the amide (VIIa) obtained, for example by reaction with BH₃ in THF. In the case where R₃ is a methyl, it is preferable to react the amines (VII) with tert-butyl dicarbonate, (BOC)₂ O, or with a mixture of formic acid and acetic anhydride, giving respectively the carbamate (VIIa, Z═OtBu) or the formamide (VIIa, Z═H), which products are then reduced, for example with LiAlH₄, to give the amines (VIIb, R₃ ═CH₃).

The secondary amines (VIIb) are then converted to the amides (Id) or ureas (Ie) according to the invention as described above.

The ketone derivatives according to the invention of formula (If): ##STR25## in which g₂, g₃, g₄, g₅ and g₆, w₂, w₃, w₄, w₅ and w₆ and R₄ and R₅ are as defined for (I), are preferably prepared from the above-described pyrazole-3-carboxylic acids (IIb) according to SCHEME 5 below: ##STR26##

The acids (IIb) are converted to the acid chlorides by the conventional methods; the latter are then converted to the ketone derivatives (If) according to the invention by reaction with an appropriate organomanganous reagent R₅ MnX₁, in which R₅ is as defined for (I) and X₁ is a halogen, preferably a chlorine atom, for example using the method described in Tetrahedron Letters, 1989, 30, 7369.

Alternatively, the ketone derivatives (If) can be prepared from the acids (IIb) via the nitriles (IIc) according to SCHEME 6 below: ##STR27##

(IIb) is converted to (IIc) by a conventional method such as, for example, conversion to the acid chloride followed by amination (NH_(3/) THF/water) and dehydration of the amide obtained, for example by treatment with CH₃ SO₂ Cl in pyridine as described in J. Am. Chem. Soc., 1955, 77, 1701.

The nitriles (IIc) obtained in this way are then treated with organometallic reagents, preferably organomagnesium reagents of the formula R₅ MgX₁, to give the ketone derivatives (If) after acid treatment.

The compounds of formula (I) obtained in this way are isolated, in the form of the free base or, where appropriate, a salt or a solvate, by the conventional techniques.

When the compound of formula (I) is obtained in the form of the free base, a salt is formed by treatment with the chosen acid in an organic solvent. Treatment of the free base, for example dissolved in an alcohol such as isopropanol, an ether such as diethylether or in acetone, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques. The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, oxalate, maleate, fumarate, naphthalene-2-sulfonate and paratoluenesulfonate, for example, are prepared in this way.

When the reaction is complete, the compounds of formula (I) can be isolated in the form of one of their salts, where appropriate, for example the hydrochloride or the oxalate; in this case, if necessary, the free base can be prepared by neutralizing said salt with a mineral or organic base such as sodium or ammonium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate, and converted into another salt such as the methanesulfonate, fumarate or naphtalene-2-sulfonate.

The acid (II'b) in which R₄ is methyl, namely 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid can for example be prepared as illustrated below in route 1 or route 2: ##STR28##

The first step is carried out according to J. Heterocyclic Chem., 1989, 26, 1389. ##STR29##

The first step is carried out according to the method described by E. S. Schweizer in J. Org. Chem., 1987, 52, 1324-1332. The second step is carried out according to the method described by R. E. Tirpak et al. in J. Org. Chem., 1982, 47, 5099-5102.

The amines of formula HNR₁ R₂ are either commercially available, or described in the literature, or prepared by known methods according to the PREPARATIONS described below.

Preferred examples of these amines are those mentioned below:

(1) bicyclo[3.2.1]octan-2-ylamine prepared according to H. Maskill et al., J. Chem. Soc. Perkin II, 1984, 119; ##STR30##

(2) bicyclo[2.2.2]octan-2-ylamine prepared according to R. Seka et al., Ber. 1942, 1379; ##STR31##

(3) endo- and exo-bicyclo[3.2.1]octan-3-ylamine prepared according to H. Maskill et al., J. Chem. Soc. Perkin Trans. II, 1984, 1369; ##STR32##

(4) endo- and exo-7-oxabicyclo[2.2.1]heptan-2-ylamine prepared according to W. L. Nelson et al., J. Heterocyclic Chem., 1972, 9, 561; ##STR33##

(5) endo-tricyclo[5.2.1.0²,6 ]decan-8-amine prepared according to G. Buchbauer et al., Arch. Pharm., 1990, 323, 367; ##STR34##

(6) endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ylamine prepared according to Ingersoll et al., J. Am. Chem. Soc., 1951, 73, 3360; ##STR35##

(7) 3-methylcyclohexylamine prepared according to Smith et al., J. Org. Chem., 1952, 17, 294; ##STR36##

(8) 2,6-dimethylcyclohexylamine prepared according to Cornubert et al., Bull. Soc. Chim. Fr., 945, 12, 367; ##STR37##

(9) 2-methoxycyclohexylamine prepared according to Noyce et al., J. Am. Chem. Soc., 1954, 76, 768; ##STR38##

(10) 4-ethylcyclohexylamine prepared according to A. Shirahata et al., Biochem. Pharmacol., 1991, 41, 205; ##STR39##

(11) bicyclo[2.2.21]oct-2-en-5-amine prepared according to H. L. Goering et al., J. Am. Chem. Soc., 1961, 83, 1391; ##STR40##

(12) N-ethyl-1-adamantylamine prepared according to V. L. Narayanan et al., J. Med. Chem., 72, 15, 443; ##STR41##

( 13 ) tricyclo[2.2.1.0², 6 ]heptan-3-ylamine prepared according to G. Muller et al., Chem. Ber., 65, 98, 1097; ##STR42##

(14) N-methyl-exo-bicyclo[2.2.1]heptan-2-ylamine prepared according to W. G. Kabalka et al., Synth. Commun., 1991, 20, 231; ##STR43##

(15) 2-azabicyclo[2.2.1]heptan-2-yl-amine prepared according to J. Am. Chem. Soc. 1982, 104, 5292, starting from 2-azabicyclo[2.2.1]heptane prepared according to Chem. Ber., 1983, 116, 1081. ##STR44##

(16) 2-azabicyclo [2.2.2]octan-2-yl-amine prepared according to J. Am. Chem. Soc. 1982, 104, 5292. ##STR45##

The amines R₃ NH₂ are commercially available or are prepared by known methods.

The acid chlorides R₂ COCl are commercially available or are prepared from the corresponding acids by known methods.

The isocyanates R₂ --N═C═O are also commercially available or are prepared from the corresponding amines (reaction with phosgene) or corresponding acids (Curtius rearrangement) by known methods.

The compounds according to the invention were subjected to biochemical tests.

The compounds (I) and their salts, where appropriate, exhibited a good affinity in vitro for the cannabinoid receptors in tests performed under the experimental conditions ,described by Devane et al., Molecular Pharmacology, 1988, 34, 605-613.

The compounds according to the invention also possess an affinity for the cannabinoid receptors present on preparations of electrically stimulated, isolated organs. These tests were performed on the guinea-pig ileum and on the mouse vas deferens according to Roselt et al., Acta Physiologica Scandinavia, 1975, 94, 142-144, and according to Nicolau et al., Arch. Int. Pharmacodyn., 1978, 236, 131-136.

In particular, the compound of formula (I) in which g₂, g₃, g₅, g₆, w₃, w₅ and w₆ are hydrogen, w₂ and w₄ are a chlorine atom, R₄ is methyl, X is a direct bond and R is 1-piperidinylamino (namely N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), or one of its pharmaceutically acceptable salts, exhibits a very good affinity for the central cannabinoid receptors. This compound is a potent and selective antagonist of the central cannabinoid receptors and has a Ki of about 2 nM. It is from 500 to 1000 times more active on the central receptor as on the peripheral receptor; it is also active upon oral administration and penetrates the blood-brain barrier. The good penetration of this compound in the central nervous system as well as its antagonist character are confirmed by the results obtained with the model of the antagonism of hypothermia induced by an agonist of cannabinoid receptors. Especially, this compound antagonizes the hypothermia induced by WIN 55 212-2 in mice with an ED₅₀ of 0.3 mg/kg i.p. and 0.4 mg/kg per os. In this test (Pertwee R. G., 1985:263-277; in Marijuana 84, Ed. Harvey, D. Y., IRL Press, Oxford), the above compound exerted its action for 8 to 10 hours after oral administration of a dose of 3 mg/kg.

In addition, the above compound, upon subcutaneous administration, improves the memory capacities of rats in the test of the central memory (A Perio et al. in Psychopharmacology, 1989, 97, 262-268).

The compounds according to the invention are generally administered in dosage units.

Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.

Thus, according to another of its features, the present invention relates to pharmaceutical compositions in which a compound of formula (I) or one of its pharmaceutically acceptable salts is present as the active principle.

The compounds of formula (I) above and their pharmaceutically acceptable salts can be used in daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 50 mg/kg. In humans, the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.0 to 1000 mg, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principles can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual and buccal administration, aerosols, implants, forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal administration.

In the pharmaceutical compositions of the present invention, the active principle is generally formulated as dosage units containing from 0.5 to 1000 mg, preferably from 1 to 500 mg, more preferably from 2 to 200 mg of said active principle per dosage unit for daily administrations.

When preparing a solid composition in the form of tablets, a wetting agent such as sodium laurylsulfate can be added to the active principle optionally micronized, which is then mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, with various polymers or other appropriate substances or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active principle with a diluent such as a glycol or a glycerol ester and pouring the mixture obtained into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methyl-paraben and propylparaben as an antiseptic, a flavoring and an appropriate color.

The water-dispersible powders or granules can contain the active principle mixed with dispersants or wetting agents, or suspending agents such as polyvinyl-pyrrolidone, and also with sweeteners or taste correctors.

Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol, butylene glycol, or polyethylene glycol.

Thus a cosolvent, for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80, can be used to prepare an aqueous solution injectable by intravenous route. The active principle can be solubilized by a triglyceride or a glycerol ester to prepare an oily solution injectable by intramuscular route.

Transdermal administration is effected using multilaminated patches or reservoirs into which the active principle is in the form of an alcoholic solution.

Administration by inhalation is effected using an aerosol containing for example sorbitan trioleate or oleic acid together with trichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas.

The active principle can also be formulated as microcapsules or microspheres, optionally with one or more carriers or additives.

Among the prolonged-release forms which are useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

The active principle can also be presented in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

The compounds of formula (I) formulated in this way can be used for the treatment of immunomodulation, migraine, asthma, epilepsy, glaucoma, Parkinson's disease, dyskinesia, neuropathy, memory and thymic disorders, vomiting, ischemia, angor, orthostatic hypotension, cardiac insufficiency, stress, anxio-depressive disorders or psychosomatic-induced disorders.

Especially, the compound of formula (Ia) in which g₂, g₃, g₅, g₆, w₃, w₅ and w₆ are hydrogen, g₄, w₂ and w₄ are a chlorine atom, R₄ is methyl, R₁ is hydrogen and R₂ is 1-piperidinyl (namely N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide), as such or optionally in the form of a pharmaceutically acceptable salt or a solvate, can be used as the active principle of drugs intended for the treatment of the diseases of the central nervous system in mammals, thanks to its remarkable properties, especially its high affinity, its selectivity towards the central receptor as well as its capacity to penetrate the blood-brain barrier.

The toxicity of the above compound is compatible with its use as a psychotropic drug, especially for the treatment of thymic disorders, anxiety disorders, mood disorders, vomiting, memory disorders, cognitive disorders, neuropathies, migraine, stress, psychosomatic-induced diseases, epilepsy, dyskinesia or Parkinson's disease.

The above compound can also be used as a drug for the treatment of appetite disorders, especially as an anorexic, for the treatment of schizophrenia, delirious disorders, psychotic disorders in general as well as for the treatment of disorders associated with the use of psychotic substances. Furthermore, the above compound can be used in cancer chemotherapy.

The use of the above compound as a drug for the treatment of appetite disorders, anxiety disorders, mood disorders, schizophrenia, psychotic disorders, memory disorders, cognitive disorders and dyskinesia, as well as its use in cancer chemotherapy, constitute a further feature of the present invention.

The following Examples illustrate the invention without however implying a limitation.

The melting or decomposition points of the products, m.p., were measured in a capillary tube with a Tottoli apparatus; in some cases, differential scanning calorimetry (DSC) was used to measure the melting temperature.

The following abbreviations are used in the preparations and in the examples:

THF: tetrahydrofuran

Et₂ O or ether: diethyl ether

iPr₂ O or iso ether: diisopropyl ether

EtOH: ethanol

AcOEt: ethyl acetate

MeOH: methanol

DCM: dichloromethane

KOH: potassium hydroxide

AcOH: acetic acid

HCl: hydrochloric acid

NaCl: sodium chloride

RT: room temperature

DSC: differential scanning calorimetry

M.p.: melting point

CH₂ Cl₂ : dichloromethane

Na₂ CO₃ : sodium carbonate

MgSO₄ : magnesium sulfate

The following abbreviations are used in the interpretation of the NMR spectra:

s: singlet

d: doublet

t: triplet

q: quadruplet

m: unresolved signals or multiplet.

The enantiomeric excess of the optically active amines, e.e., was determined by ¹⁹ F NMR after reaction with the chloride of S(+) Mosher's acid according to J. Org. Chem., 1969, 34, 2543.

The optical rotations, [α]_(D) ²⁰, were measured at c=1 in ethanol.

PREPARATIONS A. AMINES NHR₁ R₂

1. (1R,2S-endo)-(+)-Bicyclo[2.2.1]heptan-2-yl-amine

(1R,2S-endo)-(-)-Bicyclo[2.2.1]heptane-2-carboxylic acid is prepared according to Tetrahedron Letters, 1985, 26, 3095.

By means of a Curtius reaction carried out according to J. Org. Chem., 1961, 26, 3511, this is then converted to the corresponding (1R, 2S-endo)-(+)-amine.

[α]_(D) ²⁰ 32 +13.4° (c=1, EtOH).

e.e.>95%, δ(CF₃)=6.67 ppm relative to CF₃ CO₂ H.

2. (1R,2R-exo)-(-)-Bicyclo[2.2.1]heptan-2-yl-amine

The (1R,2S-endo)-(-)-bicyclo[2.2.1]heptane-2-carboxylic acid prepared in the previous Example is converted to its (1R,2R-exo)-(-) isomer according to J. Am. Chem. Soc., 1983, 105, 950, and then converted to the corresponding (1R,2R-exo)-(-)-amine as described in the previous Example.

[α]_(D) ²⁰ =-17.7° (c=1, EtOH).

e.e.>94% (determined as above, δ(CF₃)=6.81 ppm).

3. (1S,2R-endo)-(-)-Bicyclo[2.2.1]heptan-2-ylamine

(1S,2R-endo)-(+)-Bicyclo[2.2.1]heptane-2-carboxylic acid is prepared according to Tetrahedron Letters, 1989, 30, 5595, and then converted to the corresponding (1S,2R-endo)-(-)-amine as described above.

e.e.>95% (determined as above, δ(CF₃)=6.62 ppm).

4. (1S,2S-exo)-(+)-Bicyclo[2.2.1]heptan-2-ylamine

The (1S,2R-endo)-(+)-acid prepared in the previous Example is converted to its (1S,2S-exo)-(+) isomer according to according to J. Am. Chem. Soc., 83, 105, 950, and this is then converted to the corresponding (1S,2S-exo)-(+)-amine as described above.

e.e.>94% (determined as above, δ(CF₃)=6.91 ppm).

5. exo-3-Chlorobicyclo[3.2.1]oct-3-enyl-2-amine

0.4 g of PtO₂ is added to a solution of 6.1 g of exo-3-chloro-2-azidobicyclo[3.2.1]oct-3-ene, obtained according to J. Chem. Soc. Perkin Trans. II, 1984, 119, in 600 ml of ethanol and 60 ml of CHCl₃ and hydrogenation is carried out in a Parr apparatus at 4 bar and room temperature until the azide group has disappeared. After filtration on Celite, the reaction mixture is evaporated and the residue is crystallized from an ethanol/CHCl₃ mixture to give 0.49 g of the hydrochloride of the expected amine.

M.p.>240° C.

6. N-Ethyl-exo-bicyclo[2.2.1]heptan-2-ylamine

6.1. N-Acetyl-exo-bicyclo[2.2.1]heptan-2-ylamine

A solution of 3.50 ml of acetyl chloride in 10 ml of CH₂ Cl₂ is added dropwise to a solution of 5.00 g of exo-bicyclo[2.2.1]heptan-2-ylamine and 6.90 ml of triethylamine in 50 ml of CH₂ Cl₂, cooled to 0° C. After stirring for 16 hours at room temperature, the mixture is poured into 100 ml of iced water and the organic phase is separated off and washed with a 5% solution of HCl, then with water and then with a saturated solution of NaCl. After drying over MgSO₄ and evaporation of the solvents, 5.80 g of the expected acetamide are obtained.

M.p.=128° C.

6.2. N-Ethyl-exo-bicyclo[2.2.1 ]heptan-2-ylamine

A solution of 5.10 g of the above derivative in 30 ml of THF is added dropwise to a suspension of 2.18 g of LiAlH₄ in 30 ml of THF, cooled to 0° C., and the mixture is then refluxed for 8 hours. It is hydroyzed at 0° C. with 2.2 ml of water, then 2.2 ml of a 15% solution of NaOH and then 7.5 ml of water. After stirring for 15 minutes, the precipitate is filtered off and washed with THF, the filtrate is evaporated and the residue is then taken up in 50 ml of ethyl ether. This ether solution is extracted with 5% HCl; the aqueous phase obtained is neutralized with 30% NaOH and then extracted with ethyl ether. After washing with a saturated solution of NaCl, drying over MgSO₄ and evaporation, 3.82 g of a pale yellow liquid are obtained. Dissolution in ethyl ether and treatment with a soluItion of gaseous HCl in anhydrous ethyl ether gives a white precipitate, which is filtered off, washed with ethyl ether and dried under vacuum to give 4.16 g of the hydrochloride of the expected amine.

M.p.=145° C. (decomposition).

7. N-(n-Propyl)-exo-bicyclo[2.2.1]heptan-2-ylamine

7.1. N-Propionyl-exo-bicyclo[2.2.1]heptan-2-ylamine

This amide is obtained in the same way as the N-acetyl analog described in Example 6 above, using propionyl chloride instead of acetyl chloride.

7.2. N-(n-Propyl)-exo-bicyclo[2.2.1]heptan-2-ylamine

This amine is obtained starting from the above amide, in the same way as the N-ethyl analog described in the previous Example. Salification with HCl/Et₂ O in an Et₂ O/iPr₂ O mixture gives the hydrochloride of the expected amine.

M.p.=230° C. (decomposition).

8. Bicyclo[3.3.1]nonan-9-ylamine

8.1. Bicyclo[3.3.1]nonan-9-one oxime

A solution of 1.83 g of hydroxylamine hydrochloride and 2.95 g of sodium acetate in 22 ml of water is added to a solution of 2.43 g of bicyclo[3.3.1]-nonan-9-one in 9 ml of methanol and the mixture is refluxed for 24 hours. After cooling, it is extracted with ethyl ether and the organic phases are washed with a saturated solution of NaCl, then a 5% solution of Na₂ CO₃ and the water, dried over MgSO₄ and evaporated to give 3.00 g of oxime.

M.p.=151° C.

8.2. Bicyclo[3.3.1]nonan-9-ylamine

0.20 g of PtO₂ is added to a solution of 1.00 g of oxime in 250 ml of ethanol and 4 ml of CHCl₃ and hydrogenation is carried out in a Parr apparatus at 6 bar and room temperature for 18 hours. After filtration on Celite, the solvents are evaporated off and the residue is crystallized from an ethanol/heptane mixture to give 0.55 g of the hydrochloride of the expected amine.

M.p.>240° C.

EXAMPLE 1

N-(2-Adamantyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide ##STR46##

A) Sodium salt of methyl 4-chlorobenzoylpyruvate

12 g of sodium are dissolved in 250 ml of anhydrous methanol. A mixture of 64.6 ml of 4-chloroacetophenone and 67.1 ml of diethyl oxalate in 600 ml of methanol is then added, the temperature being kept below 10° C. The reaction mixture is then stirred at room temperature for 3 hours, after which 1 l of dry ether is added. Stirring is continued for 20 minutes, the mixture is filtered and the precipitate is washed with ether and dried under vacuum to give 74.6 g of the expected sodium salt.

B) Methyl 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate

A suspension of 26.3 g of the sodium salt obtained above and 23.5 g of 2,4-dichlorophenylhydrazine hydrochloride in 250 ml of acetic acid is refluxed for 4 hours. After cooling, the mixture is poured on to 250 g of ice and the crystals obtained are filtered off, washed with water and dried under vacuum to give 26.3 g of ester.

M.p.=167° C.

C) 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid

A solution of 3.70 g of KOH in 35 ml of water is added to a solution of 10.0 g of the ester obtained above in 35 ml of methanol. The mixture is refluxed for 4 hours, cooled to room temperature, poured into 100 ml of water and then neutralized with a 5% solution of HCl. The crystals obtained are filtered off, washed with water and then with pentane and dried under vacuum to give 9.50 g of acid.

M.p.=185° C.

D) 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid chloride

5.8 ml of thionyl chloride are added to a suspension of 9.50 g of the acid obtained above in 100 ml of toluene and the mixture is refluxed for 3 hours. The solvent is then evaporated off, the residue is subsequently taken up in 50 ml of toluene and the solvent is evaporated off again (procedure repeated twice) to give 8.28 g of acid chloride.

E) N-(2-Adamantyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

A solution of 0.50 g of the acid chloride obtained above in 10 ml of CH₂ Cl₂ is added dropwise to a solution of 01.30 g of adamantan-2-amine hydrochloride and 0.41 ml of triethylamine in 10 ml of CH₂ Cl₂, cooled to 0° C. The mixture is subsequently stirred at room temperature for 16 hours and then poured into 30 ml of iced water. The mixture is extracted with CH₂ Cl₂ and the organic phase is washed successively with a 5% solution of HCl, water, a 5% solution of Na₂ CO₃ and then a saturated solution of NaCl. After drying over MgSO₄ and evaporation of the solvent, the crude product is crystallized from hot benzene to give 0.32 g of white crystals.

M.p.=203° C.

EXAMPLE 2

N-(trans-4-Hydroxycyclohexyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide ##STR47##

A) trans-4-Trimethylsilyloxycyclohexylamine

A solution of 1.85 ml of chlorotrimethylsilane in 10 ml of CH₂ Cl₂ is added dropwise to a solution of 2.0 g of trans-4-hydroxycyclohexylamine hydrochloride and 4.05 ml of triethylamine in 20 ml of CH₂ Cl₂, cooled to 0° C. After stirring for 16 hours at room temperature, the mixture is hydrolyzed with water and extracted. The organic phase is washed successively with water, a 5% solution of Na₂ CO₃ and saturated NaCl. After drying over MgSO₄ and evaporation of the solvents, 1.43 g of amine (colorless liquid) are obtained.

B) N-(trans-4-Hydroxycyclohexyl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

A solution of 0.60 g of the acid chloride prepared above according to Example 1D) in 10 ml of CH₂ Cl₂ is added dropwise to a solution of 0.35 g of trans-4-trimethylsilyloxycyclohexylamine and 0.32 ml of triethylamine in 10 ml of CH₂ Cl₂, cooled to 0° C. After stirring for 16 hours at room temperature, the mixture is poured into 30 ml of iced water and extracted with CH₂ Cl₂. The organic phase is washed successively with 5% HCl and a saturated solution of NaCl and then dried over MgSO₄ and evaporated. The crude product is dissolved in 15 ml of THF; 15 ml of 5% HCl are added to the solution and the mixture is stirred for 1 hour. It is then extracted with ether and the extract is washed with water and then dried over MgSO₄, evaporated and crystallized from CH₃ OH to give 0.20 g of the expected pyrazole.

M.p.=209° C.

The compounds described in TABLES I to XII below are prepared by the procedure of EXAMPLE 1 above, starting for example from the acid or ester derivatives described below in TABLE A.

                  TABLE A                                                          ______________________________________                                          ##STR48##                                                                                                           m.p.; °C.                                                                      m.p.; °C.                  w.sub.2                                                                            w.sub.3                                                                              w.sub.4 w.sub.5                                                                            w.sub.6                                                                            g.sub.2                                                                            g.sub.4 Z = H  Z = CH.sub.3                      ______________________________________                                         H   H     CH.sub.3                                                                               H   H   H   Cl      185     98                               H   Cl    Cl      H   H   H   Cl      162    147                               H   Cl    Cl      H   H   H   CH.sub.3                                                                               188    145                               Cl  H     H       Cl  H   H   CH.sub.3                                                                               232    132                               Cl  H     H       Cl  H   H   CF.sub.3                                                                               214    179                               Cl  Cl    H       H   H   H   CH.sub.3                                                                               214    101                               H   H     CH.sub.3                                                                               H   H   Cl  Cl      188    102                               H   H     Cl      H   H   Cl  Cl      224    118                               H   H     OCH.sub.3                                                                              H   H   H   Cl      168    --                                Cl  H     Cl      H   Cl  H   Cl      255    214                               Cl  H     Cl      H   H   H                                                                                   ##STR49##                                                                             115    138                               Cl  H     Cl      H   H   H   Br      188    177                               H   H     NO.sub.2                                                                               H   H   H   CH.sub.3                                                                               106    166                               ______________________________________                                    

                                      TABLE I                                      __________________________________________________________________________      ##STR50##                         (Ia)                                         ##STR51##                                                                            ##STR52##                                                                                          ##STR53##                                           __________________________________________________________________________      3    NH(CH.sub.2).sub.2 CH.sub.3                                                                        100                                                   4                                                                                    ##STR54##          102                                                   5                                                                                    ##STR55##           60                                                   6    NH(CH.sub.2).sub.4 CH.sub.3                                                                         97                                                   7                                                                                    ##STR56##          152                                                   8                                                                                    ##STR57##          (1)                                                   9                                                                                    ##STR58##          152                                                  10                                                                                    ##STR59##          148                                                  11                                                                                    ##STR60##          162                                                  12                                                                                    ##STR61##           83                                                  13                                                                                    ##STR62##          132                                                  14                                                                                    ##STR63##          186                                                         ##STR64##          165                                                  16                                                                                    ##STR65##          134                                                  17                                                                                    ##STR66##          144                                                  18                                                                                    ##STR67##          174                                                  19                                                                                    ##STR68##          188                                                  20                                                                                    ##STR69##          120                                                  21                                                                                    ##STR70##          208                                                  22                                                                                    ##STR71##           81                                                  23                                                                                    ##STR72##          122                                                  24                                                                                    ##STR73##          188                                                  25                                                                                    ##STR74##          194                                                  26                                                                                    ##STR75##          190                                                  27                                                                                    ##STR76##          183 +14,1°                                    28                                                                                    ##STR77##          182 -14,1°                                    29                                                                                    ##STR78##          178                                                  30                                                                                    ##STR79##          191                                                  31                                                                                    ##STR80##          185 +10,2°                                    32                                                                                    ##STR81##          184 -10,6°                                    33                                                                                    ##STR82##          170                                                  34                                                                                    ##STR83##          198                                                  35                                                                                    ##STR84##          182                                                  36                                                                                    ##STR85##          188                                                  37                                                                                    ##STR86##          141                                                  38                                                                                    ##STR87##          197                                                  39                                                                                    ##STR88##          209                                                  40                                                                                    ##STR89##          164                                                  41                                                                                    ##STR90##          184                                                  42                                                                                    ##STR91##          180                                                  43                                                                                    ##STR92##          233                                                  44                                                                                    ##STR93##          220                                                  45                                                                                    ##STR94##          156 +11,7°                                    46                                                                                    ##STR95##          151 -61,6°                                    47                                                                                    ##STR96##          168                                                  48                                                                                    ##STR97##          108                                                  49                                                                                    ##STR98##          161                                                  50                                                                                    ##STR99##          154                                                  51                                                                                    ##STR100##         112                                                  52                                                                                    ##STR101##         159                                                  53                                                                                    ##STR102##         149                                                  54                                                                                    ##STR103##         125                                                  55                                                                                    ##STR104##         220                                                  57                                                                                    ##STR105##         158                                                  58                                                                                    ##STR106##         234 HCl                                              59                                                                                    ##STR107##          96                                                  60                                                                                    ##STR108##          95                                                  61                                                                                    ##STR109##         179                                                  62                                                                                    ##STR110##         172                                                  63                                                                                    ##STR111##         215 (dec) HCl                                        64                                                                                    ##STR112##         184                                                  65                                                                                    ##STR113##         195 (dec) HCl                                        66                                                                                    ##STR114##         158                                                  67                                                                                    ##STR115##         147                                                  68                                                                                    ##STR116##         186                                                  69                                                                                    ##STR117##         205 HCl                                              70                                                                                    ##STR118##         136                                                  71                                                                                    ##STR119##         208                                                  72                                                                                    ##STR120##         162                                                  73                                                                                    ##STR121##         139                                                  __________________________________________________________________________      (1) NMR spectrum of the compound of Example 8 (200 MHz, DMSO d.sup.6):         0.74 (3H, t, J = 5 Hz, CH.sub.3); 0.91 (3H, t, J = 5 Hz, CH.sub.3);            1.41-1.69 (12H, m, 6CH.sub.2); 3.43 (2H, t, NCH.sub.2); 3.66 (2H, s,           NCH.sub.2); 7.06 (1H, s, H pyrazole); 7.29 (2H, d, J = 8 Hz, H ar); 7.49       (2H, d, J = 8 Hz, H ar); 7.62-7.77 (2H, m, H ar); 7.92 (1H, d, J = 2 Hz,       ar).                                                                     

                  TABLE II                                                         ______________________________________                                          ##STR122##                   (Ia)                                              ##STR123##                                                                             ##STR124##                                                                                            ##STR125##                                     ______________________________________                                         74      NH(CH.sub.2).sub.2 CH.sub.3                                                                            95                                             75                                                                                      ##STR126##            114                                             76                                                                                      ##STR127##             59                                             77                                                                                      ##STR128##            175                                             78                                                                                      ##STR129##            178                                             79                                                                                      ##STR130##            175                                             80                                                                                      ##STR131##            147                                             ______________________________________                                    

                  TABLE III                                                        ______________________________________                                          ##STR132##                   (Ia)                                              ##STR133##                                                                             ##STR134##                                                                                            ##STR135##                                     ______________________________________                                         81                                                                                      ##STR136##            144                                             82                                                                                      ##STR137##            165                                             83                                                                                      ##STR138##            143                                             84                                                                                      ##STR139##            155                                             85                                                                                      ##STR140##            153                                             86                                                                                      ##STR141##            129                                             87                                                                                      ##STR142##            140                                             88                                                                                      ##STR143##            148                                             89                                                                                      ##STR144##            137                                             90                                                                                      ##STR145##             63                                             91                                                                                      ##STR146##            156                                             92                                                                                      ##STR147##            149 -15,1°                               93                                                                                      ##STR148##            149 +15,1°                               94                                                                                      ##STR149##            (2)                                             95                                                                                      ##STR150##             48                                             96                                                                                      ##STR151##             57                                             97                                                                                      ##STR152##            157                                             98                                                                                      ##STR153##            168                                             99                                                                                      ##STR154##            156                                             100                                                                                     ##STR155##            112                                             ______________________________________                                          (2) NMR spectrum of the compound of Example 94 (200 MHz, DMSO d.sup.6):        1.14-1.80 (10H, m, norbornyl); 2.34 (3H, s, CH.sub.3 tolyl); 3.12 (3H, sb      NCH.sub.3); 4.40 (1H, t, NCH norbornyl); 6.90 (1H, s, H pyrazole);             7.23-7.31 (2H, m, H ar); 7.71-7.77 (5H, m, H ar).                        

                  TABLE IV                                                         ______________________________________                                          ##STR156##                   (Ia)                                              ##STR157##                                                                               ##STR158##                                                                                         ##STR159##                                      ______________________________________                                         101                                                                                       ##STR160##         154                                              102                                                                                       ##STR161##         149                                              103                                                                                       ##STR162##         136                                              104                                                                                       ##STR163##         165                                              105                                                                                       ##STR164##         134                                              ______________________________________                                    

                  TABLE V                                                          ______________________________________                                          ##STR165##                   (Ia)                                              ##STR166##                                                                               ##STR167##                                                                                         ##STR168##                                      ______________________________________                                         106                                                                                       ##STR169##         205                                              107                                                                                       ##STR170##         175                                              108                                                                                       ##STR171##         214                                              109                                                                                       ##STR172##         240                                              110                                                                                       ##STR173##         124                                              111                                                                                       ##STR174##         124                                              ______________________________________                                    

                  TABLE VI                                                         ______________________________________                                          ##STR175##                   (Ia)                                              ##STR176##                                                                               ##STR177##                                                                                         ##STR178##                                      ______________________________________                                         112                                                                                       ##STR179##         215                                              113                                                                                       ##STR180##          55                                              114                                                                                       ##STR181##         168                                              ______________________________________                                    

                  TABLE VII                                                        ______________________________________                                          ##STR182##                   (Ia)                                              ##STR183##                                                                               ##STR184##                                                                                         ##STR185##                                      ______________________________________                                         115                                                                                       ##STR186##         193                                              116                                                                                       ##STR187##         168                                              117                                                                                       ##STR188##         152                                              118                                                                                       ##STR189##         216                                              119                                                                                       ##STR190##         154                                              120                                                                                       ##STR191##         102                                              ______________________________________                                    

                  TABLE VIII                                                       ______________________________________                                          ##STR192##                   (Ia)                                              ##STR193##                                                                               ##STR194##                                                                                         ##STR195##                                      ______________________________________                                         121                                                                                       ##STR196##         146                                              122                                                                                       ##STR197##         115                                              123                                                                                       ##STR198##         119                                              124                                                                                       ##STR199##         115                                              125                                                                                       ##STR200##         112                                              ______________________________________                                    

                  TABLE IX                                                         ______________________________________                                          ##STR201##                   (Ia)                                              ##STR202##                                                                               ##STR203##                                                                                         ##STR204##                                      ______________________________________                                         126                                                                                       ##STR205##         150                                              127                                                                                       ##STR206##         142                                              128                                                                                       ##STR207##         159                                              129                                                                                       ##STR208##         108                                              ______________________________________                                    

                  TABLE X                                                          ______________________________________                                          ##STR209##                   (Ia)                                              ##STR210##                                                                                ##STR211##                                                                                      ##STR212##                                        ______________________________________                                         130        NH(CH.sub.2).sub.2 CH.sub.3                                                                     144                                                131                                                                                        ##STR213##      115                                                132                                                                                        ##STR214##      123                                                133                                                                                        ##STR215##      108                                                134                                                                                        ##STR216##      120                                                135                                                                                        ##STR217##      169                                                136                                                                                        ##STR218##       68                                                137                                                                                        ##STR219##       58                                                138                                                                                        ##STR220##      182                                                139                                                                                        ##STR221##      152                                                ______________________________________                                    

                  TABLE XI                                                         ______________________________________                                          ##STR222##                                                                     ##STR223##                                                                                 ##STR224##                                                                                    ##STR225##                                         ______________________________________                                         140                                                                                         ##STR226##    260                                                 141                                                                                         ##STR227##    191                                                 142                                                                                         ##STR228##    182                                                 ______________________________________                                    

                  TABLE XII                                                        ______________________________________                                          ##STR229##                   (Ia)                                              ##STR230##                                                                            ##STR231##                                                                                       ##STR232##                                                                               ##STR233##                                                                         ##STR234##                             ______________________________________                                         143                                                                                    ##STR235##       Br        H   130                                     144                                                                                    ##STR236##       Cl        Cl  224                                     145                                                                                    ##STR237##       Br        H   148                                     146                                                                                    ##STR238##       Cl        Cl  245                                     147                                                                                    ##STR239##       Br        H   206                                     148                                                                                    ##STR240##       Cl        Cl  231                                     149                                                                                    ##STR241##       Br        H   201                                     150                                                                                    ##STR242##                                                                                       ##STR243##                                                                              H   165                                     151                                                                                    ##STR244##       Br        H   209                                     152                                                                                    ##STR245##                                                                                       ##STR246##                                                                              H   204                                     ______________________________________                                    

EXAMPLE 153

N-(2-Adamantyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide ##STR247##

A) Lithium salt of ethyl 2,4-dioxo-(4-chlorophenyl)butanoate

60 ml of a 1.0M solution of the lithium salt of hexamethyldisilazane in THF are introduced into 240 ml of anhydrous ether. The mixture is cooled to -78° C. and a solution of 10.12 g of 4-chloropropiophenone in 50 ml of ether is introduced dropwise. After stirring for 30 minutes at -78° C., a solution of 9.16 ml of diethyl oxalate in 50 ml of ether is introduced rapidly, the temperature is then allowed to rise and the mixture is stirred for 5 hours at room temperature. The pale yellow precipitate formed is filtered off, washed with ether and dried under vacuum to give 6.32 g of the expected salt.

B) Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate

This ester is obtained in the same way as in Example 1B) from the lithium salt obtained above, and is purified by recrystallization from isopropyl ether.

M.p.=105° C.

C) Compound 153

This amide is obtained from the above ester in the same way as in Example 1C), 1D) and 1E) by conversion of the ester to the acid chloride, reaction of the latter with adamantan-2-amine and purification by recrystallizaticn from isopropyl ether.

M.p.=190° C.

The amides described in TABLE XIII below are prepared by the procedure of Example 153 above.

                  TABLE XIII                                                       ______________________________________                                          ##STR248##                   (Ia)                                             Example n°                                                                           NHR.sub.2       m.p.; °C.                                  ______________________________________                                         154                                                                                          ##STR249##      78                                               155                                                                                          ##STR250##      85                                               156                                                                                          ##STR251##     148                                               157                                                                                          ##STR252##     155                                               158                                                                                          ##STR253##     201                                               ______________________________________                                    

EXAMPLE 159

N-[1-(para-Tolyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylmethyl]-N-methylcyclohexylcarboxamide ##STR254##

A) N-Methyl-1-(p-tolyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

A solution of 0.50 g of 1-(4-methylphenyl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid chloride in ml of CH₂ Cl₂ is added dropwise to 100 ml of a 33% solution of methylamine in ethanol. After stirring for hours at room temperature, the mixture is concentrated under vacuum, the residue is taken up with a mixture of 5% Na₂ CO₃ +AcOEt, the organic phase is decanted, washed with a saturated solution of NaCl and dried over MgSO₄ and the solvents are evaporated off. The residue is taken up in isopropyl ether and the crystals obtained are filtered off and dried under vacuum to give 0.44 g of the expected amide.

M.p.=138° C.

B) N-Methyl-[1-(p-tolyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methylamine

A solution of 8.76 g of the amide obtained above in 25 ml of anhydrous THF is added dropwise, at a temperature between 0° and 5° C., to 75 ml of a 1.0M solution of BH₃ in THF. After the reaction mixture has returned to room temperature, it is refluxed for 16 hours and 18 ml of 6 N HCl are then run in, while cooling with an ice bath. The mixture is stirred for 1 and a half hours at room temperature, the THF is then distilled and the residue is concentrated under vacuum. The reaction mixture is then rendered alkaline to pH 9-10 with NaOH pellets; extraction is carried out with ethyl acetate, the extract is dried over MgSO₄, the solvents are evaporated off and the crude product obtained is purified by chromatography on silica gel (300 g) using CH₂ Cl₂ /CH₃ OH 97/3 (v/v) as the eluent to give 6.0 g of amine.

M.p.=85° C.

C) Compound 159

0.62 ml of triethylamine and then a solution of 0.23 g of cyclohexanoic acid chloride in 5 ml of CH₂ Cl₂ are added successively to a solution of 0.46 g of the above amine in 10 ml of CH₂ Cl₂. After stirring for 15 minutes at room temperature, the reaction mixture is concentrated under vacuum and the residue is taken up in 30 ml of water and extracted with ethyl acetate. The organic phase is washed successively with 5% Na₂ CO₃, water and then a saturated solution of NaCl and dried over MgSO₄ and the solvents are then evaporated off. The crude product is purified by chromatography on silica gel (25 g) using toluene/AcOEt 70/30 (v/v) as the eluent. The pure product fractions are concentrated under vacuum and the residue is recrystallized from isopropyl ether to give 0.38 g of amide.

M.p.=124° C.

The amides described in TABLES XIV and XV below are prepared by the procedure of EXAMPLE 159 above.

                  TABLE XIV                                                        ______________________________________                                          ##STR255##                   (Ib)                                              ##STR256##                                                                             ##STR257##                                                                                             ##STR258##                                    ______________________________________                                         160                                                                                     ##STR259##             178                                            161                                                                                     ##STR260##             148                                            162                                                                                     ##STR261##             148                                            163                                                                                     ##STR262##             123                                            164                                                                                     ##STR263##             142                                            165                                                                                     ##STR264##             175                                            166                                                                                     ##STR265##             225                                            167                                                                                     ##STR266##             155                                            168                                                                                     ##STR267##             228                                            ______________________________________                                    

                  TABLE XV                                                         ______________________________________                                          ##STR268##                   (Ib)                                              ##STR269##                                                                              ##STR270##                                                                                          ##STR271##                                      ______________________________________                                         169                                                                                      ##STR272##          103                                              170                                                                                      ##STR273##          166                                              171                                                                                      ##STR274##          165                                              ______________________________________                                    

EXAMPLE 172

N-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylmethyl]-N'-(4-chlorophenyl)urea ##STR275##

A) 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide

This amide is obtained in the same way as in Example 159A) by reacting the acid chloride described in Example 1D) with a saturated solution of ammonia in ethanol.

M.p.=178° C.

B) [1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]methylamine

This amine is obtained in the same way as in Example 159B) by reducing the amide obtained above with BH₃ in THF.

C) Compound 172

0.20 g of 4-chlorophenyl isocyanate is added to a solution of 0.45 g of the above amine in 10 ml of toluene and the reaction mixture is stirred at room temperature for 16 hours. The solvent is evaporated off, the residue is taken up in 20 ml of ethyl acetate, washed with water and then dried over MgSO₄ and the solvents are evaporated off. The residue is purified by chromatography on silica gel (20 g) using toluene/AcOEt 60/40 (v/v) as the eluent. Concentration of the pure product fractions gives a residue, which is recrystallized from an isopropanol/isopropyl ether mixture to give 0.18 g of the expected urea.

M.p.=172° C.

The ureas described in TABLE XVI below are prepared by the procedure of EXAMPLE 172 above.

                                      TABLE XVI                                    __________________________________________________________________________      ##STR276##                         (Ic)                                        ##STR277##                                                                           ##STR278##                                                                                           ##STR279##                                                                        ##STR280##                                                                        ##STR281##                                  __________________________________________________________________________     173                                                                                   ##STR282##           Cl Cl 122                                          174                                                                                   ##STR283##           Cl Cl  88                                          175                                                                                   ##STR284##           Cl Cl 120                                          176                                                                                   ##STR285##           Cl Cl 157                                          177                                                                                   ##STR286##           Cl Cl 157                                          178                                                                                   ##STR287##           Cl Cl 138                                          179                                                                                   ##STR288##           H  CH.sub.3                                                                          183                                          180                                                                                   ##STR289##           H  CH.sub.3                                                                          148                                          __________________________________________________________________________

EXAMPLE 181

N-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]cyclohexylcarboxamide ##STR290##

A) N-(tert-Butoxycarbonyl)-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]amine

3.25 g of the 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid obtained according to Example 1C) and then 1.32 ml of triethylamine are added to a solution of 2.05 ml of diphenylphosphoryl azide in 40 ml of anhydrous t-butanol and the reaction mixture is refluxed under nitrogen for 12 hours. After cooling, it is treated with a saturated solution of NaHCO₃ and extracted with ethyl acetate. After washing with water and then with a saturated solution of NaCl, drying over MgSO₄ and evaporation of the solvents, the crude product is purified by chromatography on 70-230 mesh silica gel using CH₃ OH/CH₂ Cl₂ 1/99 (v/v) as the eluent to give 1.09 g of the expected product.

B) 1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylammonium hydrochloride

1.09 g of the above product are dissolved in 20 ml of a saturated solution of HCl in EtOH, diluted to 50%, and the reaction mixture is refluxed for 2 hours. The solvent is then evaporated off and the residue is triturated in ethyl acetate under reflux and then filtered off and dried under vacuum to give 0.55 g of the hydrochloride.

C) Compound 181

A solution of 0.11 ml of cyclohexanecarboxylic acid chloride in 2 ml of CH₂ Cl₂ is added dropwise to a solution of 0.20 g of the hydrochloride obtained in the previous Example and 0.19 ml of triethylamine in 5 ml of CH₂ Cl₂. After stirring for 24 hours at room temperature, the mixture is washed successively with a 5% solution of HCl, water, a 5% solution of Na₂ CO₃ and then a saturated solution of NaCl and dried over MgSO₄ and the solvents are then evaporated off. The crude product is crystallized from iPr₂ O to give 0.12 g of the expected amide.

M.p.=213° C.

EXAMPLE 182

N-Methyl-N-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]adamantyl-1-carboxamide ##STR291##

A) N-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]formamide

0.50 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylamine, obtained in the previous Example, is added in small portions to a mixture of 4 ml of formic acid and 0.5 ml of acetic anhydride, cooled in an ice bath. After stirring for 30 min, the solvents are evaporated off under vacuum and the residue is taken up in isopropyl ether. The white solid obtained is filtered off, washed with isopropyl ether and dried under vacuum to give 0.49 g of the expected formamide.

M.p.=181° C.

B) N-Methyl-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]amine

A solution of 1.15 g of the formamide obtained in the previous Example in 10 ml of anhydrous THF is added dropwise, at room temperature, to a suspension of 0.24 g of LiAlH₄ in 40 ml of anhydrous THF. The mixture is then refluxed for 20 minutes, cooled to 0° C. and hydrolyzed with 0.24 ml of water, then 0.24 ml of 15% NaOH and then 0.72 ml of water. After stirring for 20 minutes at room temperature, the mixture is filtered, the material on the filter is washed with THF and the filtrate is evaporated to dryness. The residue is taken up in isopropyl ether, filtered off and dried under vacuum to give 1.02 g of the expected amine.

M.p.=157° C.

C) Compound 182

By following the procedure of Example 181C), reaction of the amine obtained above with adamantane-1-carboxylic acid chloride gives the expected amide, which is purified by chromatography on a silica column using AcOEt/toluene 7:93 as the eluent.

M.p.=65° C.

                  TABLE XVII                                                       ______________________________________                                          ##STR292##                   (Id)                                             Example n°                                                                       R.sub.3  R.sub.2          m.p.; °C.                            ______________________________________                                         183      H                                                                                        ##STR293##      284                                         184      H                                                                                        ##STR294##      291                                         185      H                                                                                        ##STR295##      164                                         186      CH.sub.3                                                                                 ##STR296##      127                                         ______________________________________                                    

EXAMPLE 187

N-Methyl-[1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N'-(4-chlorophenyl)urea ##STR297##

225 mg of 4-chlorophenyl isocyanate are added to a suspension of 0.40 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-ylamine, obtained by neutralizing the hydrochloride obtained in Example 181B), in 15 ml of toluene and the mixture is heated at 40° C. for 1 hour and then left to react at room temperature for 16 hours. The precipitate obtained is filtered off, washed with toluene and dried under vacuum to give 0.46 g of the expected urea. M.p.=215° C.

EXAMPLE 188

N-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N'-(1-adamantyl)urea ##STR298##

A) A solution of 2.54 g of sodium azide in 10 ml of water is added to a solution of 10.0 g of the acid chloride obtained according to Example 1D) in 320 ml of acetone, cooled to 0° C. After stirring for 1 hour at 0° C., the precipitate obtained is filtered off, washed with acetone and then dried under vacuum to give 9.86 g of the expected acyl azide.

B) N-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-N'-(1-adamantyl)urea

A solution of 1.00 g of the acyl azide obtained in the previous Example in 5 ml of toluene is refluxed for 30 minutes. After it has returned to room temperature, the resulting solution of isocyanate is treated with 0.39 g of adamantan-1-amine and the mixture is stirred for 1 and a half hours. The precipitate obtained is filtered off, washed with toluene and then isopropyl ether and subsequently purified by trituration in an acetone/methanol mixture. After drying under vacuum, 0.48 g of the expected urea is obtained.

M.p.=244° C.

                  TABLE XVIII                                                      ______________________________________                                          ##STR299##                   (Ie)                                             Example n°                                                                         R.sub.3  R.sub.2      m.p.; °C.                              ______________________________________                                         189        H                                                                                        ##STR300##  227                                           190        CH.sub.3                                                                                 ##STR301##  144                                           ______________________________________                                    

EXAMPLE 191

1-Cyclolhexylmethyl [1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]ketone ##STR302##

2.5 ml of a 0.625M solution of MnLi₂ Cl₄ in THF (Tetrahedron, 1989, 45, 4163) are cooled to 0° C., 3.12 ml of a 0.50M solution of methylcyclohexylmagnesium bromide in THF are added dropwise and the reaction mixture is then stirred at 0° C. for 2 hours. It is then cooled to -10° C. and a solution of 0.50 g of the acid chloride prepared according to Example 1D) in 8 ml of THF is added dropwise. The mixture is stirred at room temperature for 5 hours and then hydrolyzed with a saturated solution of NH₄ Cl and extracted with ether and the extract is washed with water and then with a saturated solution of NaCl. After drying over MgSO₄ and evaporation of the solvents, the crude product is purified by chromatography on 230-400 mesh silica gel using AcOEt/hexane 5/95 (v/v) as the eluent to give 0.09 g of the expected ketone.

M.p.=118° C.

EXAMPLE 192

1-[1-(2,4-Dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazol-3-yl]-2-(4-methylphenyl)ethan-1-one ##STR303##

A) 1-(2,4-Dichlorophenyl)-3-cyano-5-(4-chlorophenyl)-pyrazole

A solution of 0.70 g of 1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide, obtained according to Example 172A), and 0.74 ml of mesyl chloride in 6 ml of pyridine is heated at 50° C. for 8 hours. The solvent is evaporated off under vacuum and the residue is dissolved in 20 ml of CH₂ Cl₂. The resulting solution is washed successively with a 5% solution of HCl, then water and then a saturated solution of NaCl and dried over MgSO₄ and the solvent is then evaporated off. The residue is crystallized from isopropyl ether to give 0.66 g of the expected nitrile.

M.p.=123° C.

B) Compound 292

6.3 ml of a 1.0M solution of 4-methylbenzylmagnesium chloride in ethyl ether are added dropwise to a solution of 0.73 g of the above nitrile in 20 ml of ethyl ether. After a reaction time of 2 hours at room temperature, the mixture is hydrolyzed with 50 ml of 5% hydrochloric acid and the resulting two-phase mixture is stirred for 30 minutes. The pink precipitate formed is filtered off, washed with water and ethyl ether and then dissolved in 100 ml of CH₂ Cl₂ and the solution is stirred for 30 minutes in the presence of about 10 g of moist silica. The silica is then filtered off, the liltrate is evaporated and the residue is crystallized from a CH₂ Cl₂ /iPr₂ O mixture to give 0.37 g of the expected ketone.

M.p.=175° C.

                  TABLE XIX                                                        ______________________________________                                          ##STR304##                   (If)                                             Example n°                                                                          R.sub.5          m.p.; °C.                                  ______________________________________                                         193                                                                                         ##STR305##      129                                               194                                                                                         ##STR306##      152                                               ______________________________________                                    

EXAMPLE 195 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide A) Lithium salt of ethyl 4-(4-chlorophenyl)-3-methyl-4-oxydo-2-oxobuten-3-oate

125 ml of a 1M solution of the lithium salt of hexamethyldisilazane in THF are added under a nitrogen atmosphere to 500 ml of ether. The mixture is cooled to -78° C. and a solution of 21 g of 4-chloropropiophenone in 100 ml of ether is added dropwise. After stirring for 45 minutes, 19.2 ml of ethyl oxalate are added rapidly and the mixture is stirred for 16 hours while allowing the temperature to rise to room temperature. The precipitate formed is filtered off, washed with ether and dried under vacuum to give 12.6 g of the expected product.

B) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylate

9.8 g of 2,4-dichlorophenylhydrazine are added to a solution of 12.6 g of the lithium salt obtained above in 70 ml of ethanol and the mixture is stirred for 16 hours at room temperature. The precipate formed is filtered off, washed with ethanol and then ether and dried under vacuum to give 12.6 g of hydrazone. This is dissolved in 100 ml of acetic acid, the mixture is refluxed for 24 hours and then poured into 500 ml of iced water. The mixture is extracted with ethyl acetate, washed with water and then a saturated solution of NaCl. After drying over magnesium sulfate and evaporation under vacuum, the crude product is crystallized from isopropyl ether to give 9.6 g of the expected product. m.p.=124° C.

C) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid

A solution of 3.3 g of KOH in 70 ml of water is added to a solution of 9.6 g of the ester obtained above in 70 ml of methanol. The mixture is refluxed for 3 hours, poured into 200 ml of iced water and the reaction mixture is acidified to pH=1 upon addition of a 10% solution of HCl. The precipitate formed is filtered off, washed with water and dried under vacuum to give 0 8.8 g of the expected acid. m.p.=211° C.

D) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride

5 ml of thionyl chloride are added to a suspension of 8.8 g of the acid obtained above in 90 ml of toluene, the mixture is refluxed for 3 hours and then evaporated to dryness under vaccum. The residue is taken up in 90 ml of toluene and the solvent is evaporated off again to give 8.0 g of the expected acid chloride which is used as such in the following step.

E) N-piperidino-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide

A solution of 8.0 g of the acid chloride obtained above in 80 ml of dichloromethane is added dropwise to a solution of 2.8 ml of 1-aminopiperidine and 3.6 ml of triethylamine in 100 ml of dichloromethane, cooled to 0° C. The reaction mixture is stirred for 3 hours while allowing the temperature to rise to room temperature and then poured into 200 ml of iced water. The mixture is extracted with dichloromethane, washed with water and then a saturated solution of NaCl, dried over MgSO₄ and evaporated under vaccum. The residue is purified by chromatography on silica gel using AcOEt/toluene (10/90; v/v) as the eluent. Crystallisation in isopropyl ether gives 5.9 g of the expected product.

m. p.=148° C.

EXAMPLE 196 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide hydrochloride

A saturated solution of gaseous HCl in ether is added dropwise to a solution of 5.9 g of the compound obtained above in 50 ml of ether until pH=1. The precipitate formed is filtered off, washed with ether and dried under vacuum to give 6.0 g of the expected hydrochloride. m.p.=224° C. (dec.).

EXAMPLE 197 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide methanesulfonate

A solution of 0..062 g of methanesulfonic acid in 2 ml of acetone is added dropwise to a solution of 0.30 g of the compound obtained in example 195 in 3 ml of acetone. The white crystals formed upon cooling to 0° C. are filtered off, washed with acetone and dried under vacuum to give 0.30 g of the expected salt. m.p.=218° C.

EXAMPLE 198 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide hemifumarate

A solution of 0.038 g of fumaric acid in 6 ml of acetone is added dropwise to a solution of 0.30 g of the compound obtained in example 195 in 3 ml of acetone. The white crystals formed upon cooling to 0° C. are filtered off, washed with acetone and dried under vacuum to give 0.23 g of the expected salt. m.p.=168° C.

EXAMPLE 199 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide hydrogensulfate

0.018 ml of concentrated sulfuric acid are added to a solution of 0.30 g of the compound obtained in example 195 in 3 ml of acetone. The white crystals formed are filtered off, washed with acetone and then ether, and dried under vacuum to give 0.31 g of the expected salt. m.p.=240° C.

EXAMPLE 200 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide paratoluenesulfonate

A solution of 0,123 g of paratoluenesulfonic acid in 6 ml of acetone is added dropwise to a solution of 0.30 g of the compound obtained in example 195 in 3 ml of acetone. The white crystals formed are filtered off, washed with acetone and dried under vacuum to give 0.34 g of the expected salt. m.p.=226° C.

The compounds described in Table XX below are prepared by the procedure of example 1 (R₄ ═H) or example 153 (R₄ ═CH₃)

                  TABLE XX                                                         ______________________________________                                          ##STR307##                                                                    EXAMPLE  R.sub.4  R.sub.2          m.p.; °C.                            ______________________________________                                         201      H                                                                                        ##STR308##      225                                         202      H                                                                                        ##STR309##      230                                         203      CH.sub.3                                                                                 ##STR310##      236                                         204      CH.sub.3                                                                                 ##STR311##                                                                                      ##STR312##                                 205      CH.sub.3                                                                                 ##STR313##      225                                         206      CH.sub.3                                                                                 ##STR314##      237                                         207      CH.sub.3                                                                                 ##STR315##      220                                         208      CH.sub.3                                                                                 ##STR316##      223                                         ______________________________________                                    

The preparation of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid, already described in example 195, steps A-C, can be improved using for example the operating conditions described in examples 209 and 210 below:

EXAMPLE 209 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid A) Lithium salt of ethyl 4-(4-chlorophenyl)-3-methyl-4-oxydo-2-oxobuten-3-oate

2008 g of the lithium salt of hexamethyldisilazane are dissolved, in a reactor, under a nitrogen atmosphere, in 10.1 l of methylcyclohexane. A solution of 1686 g of 4-chloropropiophenone in 4 l of methylcyclohexane is then added slowly at 20°±5° C. After stirring for 4 and a half hours, 1607 g of ethyl oxalate are added over 35 minutes at 20°±5° C. The mixture is stirred for 17 hours at the same temperature. The solid formed is filtered off, washed with methylcyclohexane and dried under vacuum to give 1931 g of the expected product.

B) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid

1/ 1921 g of the lithium salt obtained above are dissolved, in a reactor, under a nitrogen atmosphere, in 11 l of EtOH. 1493 g of 2,4-dichlorophenylhydrazine hydrochloride are then immediatly added at 20°±5° C. The mixture is stirred for 1 hour and 2.88 l of deionized water are then added, and stirring is continued for 17 hours at 20°±5° C. The precipitate formed is filtered off, washed with 80 % (v/v) ethanol and dried under vacuum to give 2280 g of the expected hydrazone. M.p.=140° C.

2/ 2267 g of hydrazone are dissolved, in a reactor, under a nitrogen atmosphere, in 11.3 l of toluene. 201.6 g of paratoluenesulfonic acid are then added and the mixture is refluxed for 3 hours. The mixture is cooled to 20°±5° C. and paratoluenesulfonic acid is removed by extraction with deionized water. 120.75 g of benzyltriethylammonium chloride and then a solution of 636 g of NaOH in 1180 ml of deionized water are added to the toluene solution. The mixture is heated for 4 hours at 68°±3° C. with vigorous stirring, sodium hydroxide is then neutralized and the reaction mixture is acidified with 1500 ml of HCl (d=1.19). The mixture is cooled to 20°±5° C., the precipitate formed is filtered off, washed with toluene and then deionized water, and dried under vacuum to give 1585 g of the expected product. M.p.=210° C.

EXAMPLE 210 5-(4-chlorophenyl)-1-(2,4-dichloropheny1)-4-methylpyrazole-3-carboxylic acid A) 1-(4-chlorophenyl)-1-trimethylsilyloxypropene

13.47 g of chlorotrimethylsilane are slowly added to 12.55 g of triethylamine, under a nitrogen atmosphere, at 20°±3° C. 16.86 g of 4-chloropropiophenone (endothermic mixture) and then a solution of 18.58 g of sodium iodide in 125 ml of acetonitrile are further added while maintaining the temperature at 18°±2° C. The mixture is then heated for 3 hours at 40°±5° C., the acetonitrile is removed under reduced pressure and 150 ml of toluene are added to the solid residue. 50 ml of solvent are distilled under reduced pressure to drive the residual acetonitrile off. The inorganic materials are extracted with 100 ml of iced water, the organic phase is washed with 100 ml of iced water and dried over magnesium sulfate. The toluene is removed under reduced pressure and complete removal of the solvents is performed for 15 hours at 60° C. under a pressure of 1 mbar to give 22.7 g of an oil. NMR run at 200 MHz (CDCl₃) 0.13 ppm:s:9H 1.7 ppm:d:3H 5.28 ppm:q:1H 7.21-7.39 ppm:m:4H.

B) Ethyl 3-(4-chlorobenzoyl)-3-methylpyruvate

10 g of anhydrous zinc chloride are suspended in 50 ml of toluene under a nitrogen atmosphere. Residual water is azeotropically driven off over 1 hour under atmospheric pressure. 20 ml of toluene and then 11.5 ml of ethyl ether are added to the mixture, cooled to 20°±3° C. A solution of 17 g of ethyl chloroglyoxylate diluted in 20 ml of dichloromethane is then slowly added to the mixture cooled to 0°±2° C. 14.5 g of the product obtained in the previous step are added over 1 and a half hours at the same temperature. The temperature is then allowed to rise to RT and the mixture is heated for 4 hours at 45° C. The organic phase is washed with a solution of sodium hydrogen-carbonate and then water, and dried over magnesium sulfate. The solvents are removed under reduced pressure to give 17.6 g of an oil. NMR run at 200 MHz (CDCl₃) 1.25 ppm:t:3H 1.35 ppm:d:3H 4.20 ppm:q:2H 4.93 ppm:q:1H 7.45-7.90 ppm m:4H.

C) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylate

13.3 g of 2,4-dichlorophenylhydrazine hydrochloride are added to 17.6 g of the compound obtained in the previous step and the mixture is stirred for 18 hours at 20°±3° C. Without isolating the hydrazone, 0.56 g of paratoluenesulfonic acid are then added and the ternary azeotrope (water, ethanol, toluene) is distilled. Toluene reflux is continued for 1 hour and the reaction mixture is then cooled to 20°±3° C. The insoluble material is filtered off and the toluene solution is then washed twice with 100 ml of water. The solvents are removed under reduced pressure to give a crude oil which is used as such in the next step.

D) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid

8.1 g of KOH in pellets are added to a solution of the oil obtained in the previous step in 100 ml of MeOH. The mixture is left for 1 hour at 25°±3° C. and the solvents are then removed under reduced pressure. The residue is taken up with 200 ml of water and 40 ml of toluene, the mixture is heated at 60°±3° C., decanted, and the aqueous phase is extracted three times, at this temperature, with 40 ml of toluene. Hydrochloric acid is then added to the aqueous phase until pH=1.5. The white crystals formed are filtered off, washed with water and then iso ether and dried under vaccum to give 9.9 g of the expected product. M.p.=210° C.

The compound of example 195 can also be prepared using operating conditions which are industrially more accessible, as described in example 211 below:

EXAMPLE 211 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide

A suspension of 1568.6 g of the acid obtained in step B of example 209 in 14.1 l of methylcyclohexane is heated, under a nitrogen atmosphere, to 83°±3° C., and a solution of 554.5 g of thionyl chloride in 1.57 l of methylcyclohexane is added thereto. The mixture is stirred for 3 hours at 83°±3° C. and the temperature is then increased over 2 hours up to the reflux temperature of methylcyclohexane while removing the excess thionyl chloride by distillation. The mixture is cooled to 10°±3° C. and a solution of 452.9 g of 1-aminopiperidine and 457.5 g of triethylamine in 3.14 1 of THF is then slowly added. The mixture is stirred for 17 hours while allLowing the temperature to rise to 20°±5° C., and the organic phase is successively washed, at 20°±5° C., with deionized water and a 4% aqueous solution of acetic acid. The organic phase is then washed, at 70°±3° C., with a 1.5% solution of NaOH and then deionized water, and the THF and water are driven off by azeotropic distillation under atmospheric pressure. The mixture is allowed to cool to 20°±5° C. The expected product crystallises, the precipate formed is filtered off, washed with methylcyclohexane and dried under vaccum to give 1627 g of the title compound. DSC: endothermic peak centered at 155.5° C.

EXAMPLE 212 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (solvate with ethanol)

10 g of the compound obtained in example 195 are suspended in 60 ml of absolute ethanol and the mixture is refluxed until complete dissolution of the compound. The mixture is allowed to cool to 20°±3° C. and stirring is continued for 2 hours. The white crystals formed are filtered off, washed with ethanol and dried under vacuum to give 9.6 g of the expected product. DSC: endothermic peak centered at 102.7° C. % calculated C: 56.5 H: 5.29 N: 10.98 % found C: 56.43 H: 5.41 N: 11.05.

EXAMPLE 213 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide hydrochloride (solvate with ethanol)

40 g of the compound obtained in example 196 are suspended in 400 ml of absolute ethanol. The mixture is heated to the boiling point until complete dissolution of the compound and then stirred for 20 hours while progressively cooling it to 20°±3° C. The white crystals formed are filtered off, washed with ethanol and dried under vacuum to give 29.6 g of the expected product. DSC: broad endothermic peak (175°-230° C.) Thermogravimetry: weight loss:about 8.2% starting at 100° C.

    ______________________________________                                         % calculated C: 53.04   H: 5.16   N: 10.31                                     % found      C: 52.68   H: 5.23   N: 10.34.                                    ______________________________________                                    

EXAMPLE 214 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide methanesulfonate (hemisolvate with acetone)

3.84 g of methanesulfonic acid are added at 20°±3° C. to a solution of 18.55 g of the compound obtained in example 195 in 185 ml of acetone and the mixture is stirred for 20 hours at the same temperature. The white crystals formed are filtered off, washed with acetone and dried under vacuum to give 21.65 g of the expected product. DSC: melting, recrystallisation at about 175° C. then melting at 191.5° C. Thermogravimetry: weight less:about 5.2 % starting at 90° C.

    ______________________________________                                         % calculated C: 49.90   H: 4.75   N: 9.50                                      % found      C: 49.70   H: 4.76   N: 9.44.                                     ______________________________________                                    

EXAMPLE 215 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide paratoluenesulfonate

7.61 g of paratoluenesulfonic acid are added at 20°±3° C. to a solution of 18.55 g of the compound obtained in example 195 in 185 ml of acetone and the mixture is stirred for 20 hours at the same temperature. The white crystals formed are filtered off, washed with acetone and dried under vacuum to give 24.25 g of the expected product. DSC: endothermic peak centered at 236.8° C.

    ______________________________________                                         % calculated C: 54.16   H: 4.60   N: 8.72                                      % found      C: 54.11   H: 4.71   N: 8.69.                                     ______________________________________                                    

EXAMPLE 216 N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide dihydrogenphosphate

4.61 g of 85% phosphoric acid are added at 20°±3° C. to a solution of 18.55 g of the compound obtained in example 195 in 185 ml of methylethylketone. Water is removed by distillation under atmospheric pressure of the azeotrope methylethylketone/water. The mixture is progressively cooled to 20°±3° C. while stirring for 20 hours. The white crystals formed are filtered off, washed with methylethylketone and dried under vacuum to give 21 g of the expected product. DSC: endothermic peak centered at 185.5° C.

    ______________________________________                                         % calculated C: 47.04   H: 4.31   N: 9.97                                      % found      C: 46.96   H: 4.62   N: 9.98.                                     ______________________________________                                     

What is claimed is:
 1. A compound of the formula ##STR317## in which g₂, g₃, g₄, g₅ and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical or different and are independently hydrogen, a chlorine or bromine atom, a (C₁ -C₃)-alkyl, a (C₁ -C₃)-alkoxy, a trifluoromethyl or a nitro group and g₄ is optionally a phenyl group;R₄ is hydrogen or a (C₁ -C₃)-alkyl; X is either a direct bond or a group --(CH₂)_(x) --N(R₃)--, in which R₃ is hydrogen or a (C₁ -C₃)-alkyl and x is zero or one; and, R isa group --NR₁ R₂ in which R₁ and R₂ are independently a (C₁ -C₆)-alkyl; an optionally-substituted non-aromatic (C₃ -C₁₅) carbocyclic radical; an amino (C₁ -C₄) alkyl group in which the amino is optionally disubstituted by a (C₁ -C₃)-alkyl; a cycloalkyl-(C₁ -C₃) alkyl in which the cycloalkyl is C₃ -C₁₂ ; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, by a (C₁ -C₅)-alkyl or by a (C₁ -C₅)-alkoxy; a phenyl (C₁ -C₃)-alkyl; a diphenyl-(C₁ -C₃)-alkyl; a naphthyl; an anthracenyl; a saturated 5- to 8-membered heterocyclic radical which is unsubstituted or substituted by a (C₁ -C₃)- alkyl, by a hydroxyl or by a benzyl group; a 1-adamantylmethyl; an aromatic heterocycle unsubstituted, mono- or polysubstituted by a halogen, a (C₁ -C₅)-alkyl, a (C₁ -C₅)-alkoxy; a (C₁ -C₃)-alkyl substituted by an aromatic heterocycle unsubstituted or mono- or polysubstituted by a halogen, a (C₁ -C₅) alkyl, a (C₁ -C₅)-alkoxy, or else R₁ is hydrogen and R₂ is as defined above, or else R₁ and R₂, together with the nitrogen atom to which they are bonded,form a saturated 5- to 8-membered heterocyclic radical, said heterocyclic radical being other than morpholine when w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ are all hydrogen; a group R₂ as defined above when X is --(CH₂)_(x) N(R₃)--; or a group R₅ when X is a direct bond, R₅ being a (C₁ -C₃)-alkyl; a (C₃ -C₁₂)-cycloalkyl which is unsubstituted or substituted by a (C₁ -C₅)-alkyl; a phenyl-(C₁ -C₃)-alkyl which is unsubstituted or substituted by a halogen or by a (C₁ -C₅)-alkyl; a cycloalkyl-(C₁ -C₃)-alkyl in which the cycloalkyl is C₃ -C₁₂ and is unsubstituted or substituted by a (C₁ -C₅)-alkyl; or a 2-norbornylmethyl;or one of its salts.
 2. A compound according to claim 1 of the formula ##STR318## in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ are as defined for (I) in claim 1, R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a non-aromatic (C₃ -C₁₅) carbocyclic radical or a saturated 5- to 8-membered heterocyclic radical selected from 1-pyrrolidinyl, 1- piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl, or one of its salts.
 3. A compound according to claim 1 of the formula ##STR319## in which R₄, X and R are as defined for (I) in claim 1, or one of its salts.
 4. A compound of formula (i) according to claim 3 in which R₄ is hydrogen or a methyl group, or one of its salts.
 5. A compound of formula (i) according to claim 3 in which R₄ is hydrogen or methyl and X is a direct bond, or one of its salts.
 6. A compound of formula (i) according to claim 3 in which R₄ is hydrogen or methyl, X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen or a methyl group and R₂ is a non-aromatic C₃ -C₁₅ carbocyclic radical or a saturated 5- to 8-membered heterocyclic radical selected from 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-morpholinyl and 4-thiomorpholinyl, or one of its salts.
 7. A compound which is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide, or one of its salts or solvates thereof.
 8. A compound according to claim 7 wherein said salts or solvates are selected from the group consisting of the hydrochloride or its solvate with ethanol, the methanesulfonate or its hemisolvate with acetone, the hemifumarate, the hydrogensulfate, the paratoluenesulfonate and the dihydrogenphosphate.
 9. A compound of formula (i) according to claim 3 in which R₄ is hydrogen or methyl, X is --(CH₂)_(x) --N(R₃)-- and R is --NR₁ R₂, x is zero or one, R₃ is hydrogen or a methyl group, R₁ is hydrogen and R₂ is a phenyl which is unsubstituted or substituted by one or two halogen atoms, a (C₁ -C₅)-alkyl group or a (C₁ -C₅)-alkoxy group, or a non-aromatic (C₃ -C₁₅) carbocyclic radical, or one of its salts.
 10. A compound according to claim 1 of the formula ##STR320## in which X and R are as defined for (I) in claim 1 and w₄ is a methyl group or a methoxy group, or one of its salts.
 11. A compound of formula (ii) according to claim 10 in which w₄ is methyl or methoxy, X is a direct bond and R is a group --NR₁ R₂ in which R₁ is hydrogen or a methyl group and R₂ is a non-aromatic (C₃ -C₁₅) carbocyclic radical, or one of its salts.
 12. A compound of formula (ii) according to claim 10 in which w₄ is methyl or methoxy, X is a group --(CH₂)_(x) --N(R₃)-- in which x is zero or one and R₃ is hydrogen or a methyl group, and R is a group --NR₁ R₂ in which R₁ is hydrogen and R₂ is a phenyl which is unsubstituted or substituted by one or two halogen atoms, a (C₁ -C₅)-alkyl group or a (C₁ -C₅)-alkoxy group, or a non-aromatic (C₃ -C₁₅) carbocyclic radical, or one of its salts.
 13. A compound of formula (I) according to claim 1 in which w₂, w₃, w₄, w₅ and w₆, g₂, g₃, g₄, g₅ and g₆ and R₄ and X are as defined for (I) in claim 1 and R is a group --NR₁ R₂ in which R₁ is hydrogen or a (C₁ -C₆)-alkyl group and R₂ is a 2- or 3-indolyl-(C₁ -C₃)-alkyl group or a 2- or 3-indolyl group, or one of its salts.
 14. A compound according to claim 1 of the formula ##STR321## in which X is as defined for (I) in claim 1, R is a group --NR₁ R₂ in which R₁ is hydrogen or a (C₁ -C₆)-alkyl and R₂ is a 2- or 3-indolyl-(C₁ -C₃)-alkyl group or a 2or 3-indolyl group, and either w₂ is hydrogen and w₄ is a methyl or methoxy group or w₂ and w₄ are a chlorine atom, or one of its salts.
 15. A compound according to claim 1 of the formula ##STR322## in which X and R are as defined for (I) in claim 1 and g₄ is a bromine atom or a methyl or trifluoromethyl group, or one of its salts.
 16. A compound of the formula ##STR323## in which R₄ is as defined for (I) in claim 1 and Alk is a (C₁ -C₅)-alkyl.
 17. A pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula (I) according to claim 1 or one of its pharmaceutically acceptable salts, mixed with at least one pharmaceutically acceptable excipient.
 18. A pharmaceutical composition according to claim 17, which is in the form of a dosage unit.
 19. A pharmaceutical composition according to claim 18, containing from 0.5 to 1000 mg of active principle.
 20. A pharmaceutical composition according to claim 17, wherein the active principle is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide, or one of its pharmaceutically acceptable salts or solvates thereof.
 21. A compound according to claim 1, wherein:g₂, g₃, g₄, g₅ and g₆ and w₂, w₃, w₄, w₅ and w₆ are identical or different and are independently hydrogen, a chlorine or bromine atom, a (C₁ -C₃)alkyl, a (C₁ -C₃)alkoxy, a trifluoromethyl or a nitro group and g₄ is optionally a phenyl group; R₄ is hydrogen or a (C₁ -C₃)alkyl; andeither: (a) X is a direct bond, and R is:(i) a group --NR₁ R₂ in which R₁ is hydrogen; a (C₁ -C₅)alkyl or a non-aromatic (C₃ -C₁₅)carbocyclic radical and R₂ is a (C₁ -C₆)alkyl; a non-aromatic (C₃ -C₁₅)carbocyclic radical optionally substituted by at least a (C₁ -C₅)alkyl, a (C₁ -C₅)alkoxy, a halogen and/or a hydroxy; an amino(C₁ -C₄)alkyl group in which the amino is disubstituted by a (C₁ -C₃)alkyl; a (C₃ -C₁₂)cycloalkyl(C₁ -C₃)alkyl; a phenyl which is unsubstituted or monosubstituted by a halogen or a (C₁ -C₅)alkyl; a phenyl(C₁ -C₃)alkyl; a diphenyl(C₁ -C₃)alkyl; a saturated 5- to 8-membered heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidyl, morpholinyl, hexahydroazepinyl, quinuclidinyl, oxabicycloheptanyl, azabicyclo[2.2.1]heptanyl and azabicyclo[2.2.2]octanyl, unsubstituted or substituted by a (C₁ -C₃)alkyl or a benzyl group; or a (C₁ -C₃)alkyl substituted by an aromatic heterocycle selected from the group consisting of pyrrolyl, pyridyl and indolyl, unsubstituted or monosubstituted by a (C₁ -C₅)alkyl; or else R₁ and R₂, together with the nitrogen atom to which they are bonded, form a saturated 5- to 8-membered heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidyl and morpholinyl, said heterocyclic radical being other than morpholine when w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ are all hydrogen; or (ii) a group R₅, R₅ being a phenyl(C₁ -C₃)alkyl in which the phenyl is substituted by a (C₁ -C₅)alkyl; a (C₃ -C₁₂)cycloalkyl(C₁ -C₃)alkyl; or a 2-norbornylmethyl;or (b) X is a group --(CH₂)_(x) --N(R₃)-- in which R₃ is hydrogen or a (C₁ -C₃)alkyl and x is zero or one and R is:(i) a group --NR₁ R₂ in which R₁ is hydrogen and R₂ is a non-aromatic (C₃ -C₁₅)carbocyclic radical or a phenyl which is unsubstituted or mono- or disubstituted by a halogen, a (C₁ -C₅)alkyl or a (C₁ -C₅)alkoxy; or (ii) a group R₂, R₂ being a non-aromatic (C₃ -C₁₅)carbocyclic radical; a phenyl substituted by a halogen; an anthracenyl; or an indolyl optionally substituted by a (C₁ -C₅)alkoxy;or one, of its salts.
 22. A compound according to claim 1, wherein X is a direct bond and R represents:(i) a group --NR₁ R₂ in which R₁ is hydrogen; a (C₁ -C₆)alkyl or a non-aromatic (C₃ -C₁₅)carbocyclic radical and R₂ is a (C₁ -C₆)alkyl; a non-aromatic (C₃ -C₁₅)carbocyclic radical optionally substituted by at least a (C₁ -C₅)alkyl, a (C₁ -C₅)alkoxy, a halogen and/or a hydroxy; an amino(C₁ -C₄)alkyl group in which the amino is disubstituted by a (C₁ -C₃)alkyl; a (C₃ -C₁₂)cycloalkyl(C₁ -C₃)alkyl; a phenyl which is unsubstituted or monosubstituted by a halogen or a (C₁ -C₅)alkyl; a phenyl(C₁ -C₃)alkyl; or a diphenyl(C₁ -C₃)alkyl; or (ii) a group R₅, R₅ being a phenyl(C₁ -C₃)alkyl in which the phenyl is substituted by a (C₁ -C₅)alkyl; a (C₃ -C₁₂)cycloalkyl(C₁ -C₃)alkyl; or a 2-norbornylmethyl;or one of its salts.
 23. A compound according to claim 1, wherein X is a direct bond and R represents a group --NR₁ R₂ in which R₁ is hydrogen; a (C₁ -C₆)alkyl or a non-aromatic (C₃ -C₁₅)carbocyclic radical and R₂ is a saturated 5- to 8-membered heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidyl, morpholinyl, hexahydroazepinyl, quinuclidinyl, oxabicycloheptanyl, azabicyclo[2.2.1]heptanyl and azabicyclo[2.2.2]octanyl, unsubstituted or substituted by a (C₁ -C₃)alkyl or a benzyl group; or else R₁ and R₂, together with the nitrogen atom to which they are bonded, form a saturated 5- to 8-membered heterocyclic radical selected from the group consisting of pyrrolidinyl, piperidyl and morpholinyl, said heterocyclic radical being other than morpholine when w₂, w₃, w₄, w₅ and w₆ and g₂, g₃, g₄, g₅ and g₆ are all hydrogen;or one of its salts.
 24. A compound according to claim 1, wherein X is a direct bond and R represents a group --NR₁ R₂ in which R₁ is hydrogen; a (C₁ -C₆)alkyl or a non-aromatic (C₃ -C₁₅)carbocyclic radical and R₂ is a (C₁ -C₃)alkyl substituted by an aromatic heterocycle selected from the group consisting of pyrrolyl, pyridyl and indolyl, unsubstituted or monosubstituted by a (C₁ -C₅)alkyl; or one of its salts.
 25. A compound according to claim 1, wherein X is a group --(CH₂)_(x) --N(R₃)-- in which R₃ is hydrogen or a (C₁ -C₃)alkyl and x is zero or one and R is:(i) a group --NR₁ R₂ in which R₁ is hydrogen and R₂ is a non-aromatic (C₃ -C₁₅)carbocyclic radical or a phenyl which is unsubstituted or mono- or disubstituted by a halogen, a (C₁ -C₅)alkyl or a (C₁ -C₅)alkoxy; or (ii) a group R₂, R₂ being a non-aromatic (C₃ -C₁₅)carbocyclic radical; a phenyl substituted by a halogen; an anthracenyl; or an indolyl optionally substituted by a (C₁ -C₅)alkoxy;or one of its salts.
 26. A pharmaceutical composition according to claim 18, wherein the active princiiple is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, or one of its pharmaceutically acceptable salts or a solvate thereof.
 27. A pharmaceutical composition according to claim 19, wherein the active principle is N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, or one of its pharmaceutically acceptable salts or a solvate thereof.
 28. A pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula (I) according to claim 1, or one of its pharmaceutically acceptable salts, mixed with at least one pharmaceutically acceptable excipient.
 29. A pharmaceutical composition according to claim 29 which is in the form of a dosage unit.
 30. A pharmaceutical composition according to claim 29 containing from 0.5 to 1000 mg of active principle. 